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TODAY’S RESEARCH TOMORROW’S CURE National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH Year 2007-2010

Division of Cellular and Molecular Research

Division of Medical Sciences

Division of Clinical Trials and Epidemiological Sciences

Clinician-Investigators & Scientists


contents:

02 > DIRECTOR’S MESSAGE 03 > NCCS BOARD MEMBERS 04 > NCCS RESEARCH COMMITTEE 05 > AWARDS AND ACHIEVEMENTS - NEW APPOINTMENTS 16 > DIVISION OF CELLULAR AND MOLECULAR RESEARCH 34 > DIVISION OF MEDICAL SCIENCES 56 > DIVISION OF CLINICAL TRIALS AND EPIDEMIOLOGICAL SCIENCES 62 > CLINICIAN INVESTIGATORS AND SCIENTISTS 80 > PUBLICATIONS 140 > HUMPHREY OEI DISTINGUISHED LECTURE SERIES 147 > RESEARCH SUPPORT GROUPS


DIRECTOR’S MESSAGE

Medical science has made many rapid developments. Each day unfolds new insights which give doctors a better understanding of diseases and their behaviourial patterns. The National Cancer Centre Singapore, as a leading cancer centre in Asia, is proud to be among the many centres which have been contributing towards this pool of knowledge. I am pleased that we have many dedicated and committed scientists and researchers in NCCS whose good work are often not visible to the public eye. Many of their research findings have helped our oncologists and other specialists to improve on our diagnosis and treatment for our cancer patients. Our findings have been published in internationally recognised peer-reviewed medical journals and won acclaims at overseas conferences. This is what sets NCCS apart from other cancer treatment centres. NCCS recognises that the fight against cancer cannot be undertaken alone. We are networking and collaborating with other leading research centres to work on various projects from India to Europe and the US. Top scientists are continually invited to our laboratories just as we send out researchers and doctors to gain exposure overseas. Apart from retaining and recruiting talents, there is also the need to acquire the latest technology and equipment. Funding for research projects is another hurdle that we must overcome. We welcome your support to be a part of the team and share our noble goal to free our future generation from the clutches of cancer. At least we can say we have a purpose in our life. Professor Soo Khee Chee Director National Cancer Centre Singapore

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NCCS BOARD MEMBERS

National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

NCCS RESEARCH FUND BOARD OF TRUSTEES CHAIRMAN Dr Charles TOH Consultant Cardiologist, Charles Toh Clinic MEMBERS Ms Viviana BERNARD Mr LEE Kim Shin Partner, Allen and Gledhill LLP Mr LIM Beng Hua Mr NG Boon Yew Chairman, Raffles Campus Pte Ltd Mr SIM Kee Boon (till 9th November 2007) Director, Temasek Holdings Pte Ltd Prof SOO Khee Chee Director, National Cancer Centre Singapore Mr Nicky TAN Director, Ntan Corporate Advisory Pte Ltd Prof TAN Ser Kiat Group Chief Executive Officer, Singapore Health Services

NCCS SCIENTIFIC ADVISORY BOARD Professor Kie Kian ANG Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, USA Professor Malcolm K. BRENNER Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Professor Anthony R. MEANS Cancer Biology Program, Duke University, Durham, USA Professor Alan P. VENOOK Division of Medical Oncology, University of California, San Francisco, USA Prof Arnold J LEVINE (from 2007 - 2010) Institute for Advanced Study, Princeton

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NCCS RESEARCH COMMITTEE CHAIRMAN Prof KON Oi Lian Head, Division of Medical Sciences MEMBERS Prof HUI Kam Man Head, Division of Cellular and Molecular Research Dr Joseph WEE Head, Division of Clinical Trials and Epidemiological Sciences Prof TEH Bin Tean Group Director, Translational Research, SingHealth Prof David M. VIRSHUP Program Director, Cancer & Stem Cell Biology, Duke-NUS Graduate Medical School Dr CHUA Eu Tiong Head, Department of Radiation Oncology A/Prof Cynthia GOH Head, Department of Palliative Medicine Dr James KHOO Head, Department of Oncologic Imaging A/Prof KOONG Heng Nung Head, Department of Surgical Oncology Dr TOH Han Chong Head, Department of Medical Oncology Dr TAN Eng Huat Department of Medical Oncology (Research) Dr TAN Hiang Khoon Department of Surgical Oncology (Research) Ms Audrey-Anne OEI Senior Manager, Research Administration MEMBERS (Ex-Officio) Prof SOO Khee Chee Director Dr Vijay Kumar SETHI Chairman, Medical Board Dr KOO Wen Hsin Deputy Director Prof London Lucien OOI Adviser Dr Nicholas TAY Chief Operating Officer > 04


Awards And Achievements New Appointments


AWARDS AND ACHIEVEMENTS

The 1GCEO Excellence Award is the highest honour for staff excellence presented by SingHealth to outstanding staff who are role models in their respective fields, and Prof Hui Kam Man is indeed a notable character in his field of research. Leading the Division of Cellular and Molecular Research, Prof Hui has contributed significantly to the evolution of NCCS to a world renowned cancer centre which integrates research and clinical care with the ultimate goal of benefiting patients.

Dr N Gopalakrishna Iyer was awarded the 2Michael E Burt Memorial Award in 2010, a prestigious award conferred by one of the world’s premier cancer centres, Memorial Sloan-Kettering Cancer Center in US. Dr Gopal, a surgical oncologist, was given the award for superior clinical and operative skills, research and commitment to education. This award is given annually to the best overall Fellow in the entire division of surgery.

Prof Soo Khee Chee was awarded the 3National Outstanding Clinician Mentor Award by the Ministry of Health in 2008 for his outstanding contribution to the healthcare industry. Also the Director of the National Cancer Centre Singapore, Prof Soo is well-respected in all aspects of clinician mentorship, training up young clinicians, setting up a conducive clinical and research environment, and also leading a team to develop a world-class cancer centre.

Dr Daniel Tan was the first Singaporean to receive the Young Investigator Award from the 4ASCO Cancer Foundation in 2009. His research project will focus on nose cancer, which is uncommon in the West but more prevalent among Asians. The project will attempt to find out how a targeted drug works in nasopharyngeal cancer. In the subsequent year, Dr Daniel Tan was conferred the Merit Award by 4ASCO for his exploration of a new anti-cancer compound in a Phase I trial. Dr Tan was the primary fellow in charge of a trial that tested for the safety and toxicity of a novel agent used for the first time in human bodies while at the UK’s Royal Marsden Hospital on a National Medical Research Council (NMRC) fellowship.

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Dr Iain Tan was awarded the Young Investigator Award by 4ASCO in 2010 for his research on gastric cancer. Working on the premise that gastric cancer is the second leading cause of global cancer mortality, Dr Tan identified two genetic sub-types of gastric cancer with different responses to drugs. He was also the only doctor to have attained this award while doing his research in an institution outside of North America.

Dr Tan Min-Han was awarded the 5ASEAN Youth Award for Science and Technology in 2010 for scientific excellence and his ability to inspire the next generation. A leader in clinical care and research in patients at elevated genetic risk of kidney, breast and testicular cancer, his focus is on the practical application of technology, including genomic profiling and circulating tumor cell isolation, on immediate patient care."

Prof Teh Bin Tean, the recipient of the Singapore Translational Research Investigator Award (STaR) bestowed by 6NMRC in 2009, is one of the world’s leading kidney cancer research scientists and a pioneer in molecular profiling of kidney cancer. In 2007, he was appointed the founding director of the NCCSVARI laboratory, which serves as a bridge between translational research and clinical medicine both at the National Cancer Centre Singapore (NCCS) and at Van Andel Research Institute (VARI).

Dr Marissa Teo was awarded the 7Unesco-L’Oreal for Women in Science International Fellowship in 2010. She was the first Singaporean to receive this award which was first given out 12 years ago. Her research work will focus on treating patients with nasopharyngeal carcinoma, which is prevalent in southern China and South-east Asia, by combining chemotherapy with cell therapy.

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AWARDS AND ACHIEVEMENTS

Dr Toh Han Chong was awarded the Clinician Scientist Award (Investigator level) by 6NMRC in 2009 for his research on Nasopharyngeal Cancer (NPC). Dr Toh’s research involves a clinical trial to treat newly diagnosed patients with advanced NPC, and will examine ways to leverage the immune system, or the killer T-cells that it contains, to fight the NPC cells that contain Epstein-Barr Virus (EBV) proteins. This clinical trial led by Dr Toh is expected to have potential breakthroughs in helping NPC patients improve their clinical outcomes and their quality of life.

Dr Joseph Wee was awarded the Clinician Scientist Award (Senior Investigator level) from the 6NMRC in 2009 for his research on Nasopharyngeal Cancer (NPC). Dr Wee's research focuses on a phase 3 clinical trial to test the effectiveness of treating NPC using three chemotherapy drugs. The cancer of the upper throat or pharynx afflicts about 400 people each year in Singapore, mostly men aged 40 to 60.

Prof Wong Meng Cheong was awarded the Clinician Scientist Investigator (Senior Clinician Scientist) Award from 6NMRC in 2007 for his project titled as “Working on DNA damage repair signalling, brain tumour stem cells, biological agents and immunotherapy for brain tumour relapsed patients”. His research focuses on improving diagnostic and treatment modalities for patients suffering from brain disease.

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Year 2010 Recipient

Award

Project

Dr Huang Dachuan

8

AACR Scholar-inTraining Award

“BIRB796, p38o inhibitor inhibits cholangiocarcinoma cell migration in a p53dependent manner”

Dr Iain Tan

8

AACR Scholar-inTraining Award

“Genomic Profiles of Gastric Cancer Predict Clinical Prognosis and May Guide Treatment Selection”

Recipient

Award

Project

Dr Claramae Chia

9

SMF Scholarship Award

“Identification of novel biomarkers in predicting metastases and prognosis of nasopharyngeal carcinoma using genes that correlate with a metastatic phenotype”

Dr Ravindran Kanesvaran

Merit Award at the 4ASCO Genitourinary Symposium 2009

“Comparison of the UISS and SSIGN scoresfor survival prediction in Asian patients with clear cell carcinoma”

Dr Richard Quek

6 NMRC Medical Research Fellowship Award

“Translational therapeutics: application of novel insights from basic molecular and biochemical research to the rationale development of molecularly-targeted anti-cancer therapy”

Ms Tan Hwei Ling

10

Dr Iain Tan

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National Research Foundation – Ministry of Health Healthcare Research Scholarship

“Predictive and prognostic biomarkers in gastric cancers – towards individualized therapy”

Dr Melissa Teo Ching Ching

6

NMRC Medical Research Fellowship Award

“A study of two cancer care systems: Ontario and Singapore”

Dr Wong Nan Soon

NMRC Medical Research Fellowship Award

“Phase I clinical trial design and implementation/ investigational new drug development in oncology”

Year 2009

SGH 18th Annual Scientific “Integrated Genomic Profiles Reveal Therapeutic Meeting - Young Pathways and Biomarkers for Chromophobe Investigator's Award Renal Cell Carcinoma and Oncocytoma” (Basic Science) Finalist.

6

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AWARDS AND ACHIEVEMENTS

Year 2008

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Recipient

Award

Project

Dr Chew Joon Lin

9

SMF Post-Doctoral Scholarship Award

“The role of stem-cell regulatory factors in the tumorigenesis and metastasis of human pancreatic cancer”

Mr William Chin Wei Lim

10

SGH 17th Annual Scientific Meeting Best Oral Paper (Scientist)

“Membrane Transport Enhancement of Chlorin e6 – Polyvinylpyrrolidone and its Photodynamic Efficacy on the Chick Chorioallantoic Model”

Dr Lee Ser Yee

9

“Analysis of molecular alterations in human pancreatic adenocarcinoma using immunohistochemistry and gene expression profiling”

Mr Lin Yingbo, Mr William Chin, A/Prof Malini Olivo

Singapore Science and Engineering Fair - Silver Award

“Transport Enhancement and Improved Selectivity of Chlorin e6 polyvinylpyrrolidone on the chorioallantoic tumor model”

Dr Grace Pang Su Yin

9

SMF Scholarship Award

“The effect of single nucleotide polymorphisms in the opioid receptor”

Dr Daniel Tan

6

NMRC Medical Research Fellowship Award

“Accelerating molecularly targeted drug through rational design of hypothesis-testing early clinical trials”

4

Merit Award: ASCO-NCI -EORTC Annual meeting on Molecular Markers in Cancer, Florida

“Why excision repair cross complementing-1 (ERCC1) cannot yet be used to personalize chemotherapy regimens in advanced non-small cell lung carcinoma (aNSCLC): a systematic review”

SMF Scholarship Award

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Dr Tan Min-Han

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National Youth Council Singapore Youth Award, Science and Technology

-

Mr Wang Zihua

14

Chinese Government National Award for Outstanding Self-Financed Students Abroad

-


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Year 2007 Recipient

Award

Dr Ang Mei-Kim

9

Ms Cheng Shi Yuan

10

Mr William Chin Wei Lim

9

SMF Scholarship Award

“Targeted delivery of photosensitizer using biomedical polymers for biophotonic therapeutics and diagnostics of cancer”

Dr Dulloo Muhammad Iqbal

9

SMF Scholarship Award

“Elucidating the mechanisms regulating the stability of p73, the homologue of the tumor suppressor p53”

Dr Kang Khong Bee

SMF Post-Doctoral Scholarship Award

Mr Leong Siew Hong

9

Dr Ooi Aik Seng

9

SMF Post-Doctoral Scholarship Award

“The extracellular signaling pathway that mediates the vasculature reorganization in the arrival of metastatic cancer cells”

Dr Pang Su Yin Grace

NMRC Medical Research Fellowship Award

“To screen for variant SNPs in genes encoding opioid drug receptors in Asian cancer patients and to identify functional SNPs and to determine their influence on the PK/PD of opiods in cancer patients”

Dr Felicia Tan Li Sher

9

SMF Scholarship Award

“Analysis of Immunohistochemistry and Gene Expression in Human Cholangiocarcinomas”

Dr Tan Min-Han

9

SMF Scholarship Award

“Molecular genetics of clear cell renal cell carcinoma”

Dr Tan Poi Kiang

9

SMF Post-Doctoral Scholarship Award

“Selective gene transfer into human brain tumors by using MG11-mediated adenoviral vectors with native tropism”

Ms Tan Sze Huey

6 NMRC Medical Research Scientist Award

“Sensitivity analysis for an Asthma Trial with Missing Data”

Dr Marissa Teo

SMF Post-Doctoral Scholarship Award

“Tumor suppressor network in hepatocellular carcinoma”

SMF Scholarship Award

Project “Immunohistochemical analysis and gene expression profiling in peripheral T-cell lymphomas”

SGH 16th Annual Scientific “Identifying RhoGEF Ect2 as a novel drug target Meeting - Young for synergistic therapy with irradiation and Investigator's Award chemotherapy in malignant gliomas” (Basic Science)

9

SMF Scholarship Award

6

9

“Radioresistance of brain tumor stem cells”

“miRNA expression profiling and functional analysis in gastric cancer”

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AWARDS AND ACHIEVEMENTS

Abbreviation and Award Summary 1Singhealth GCEO Excellence Award In recognition of outstanding contribution to research in SingHealth. 2Memorial Sloan-Kettering Cancer Center Michael E Burt Memorial Award A prestigious award given by Memorial Sloan-Kettering Cancer Center annually to the best overall fellow in the entire division of surgery. 3National

Outstanding Clinician Award This award recognizes individuals who have contributed substantially in the training of young clinicians and clinician scientists via mentorship or by virtue of academic positions. 4ASCO - American Society of Clinical Oncology ASCO Merit Award: ASCO-NCI-EORTC Annual meeting on Molecular Markers in Cancer 2008, Florida – The award is designed to promote clinical research by young scientists and provide fellows with an opportunity to present their research and interact with other clinical cancer investigators at ASCO scientific meetings.

Young Investigator Award - to provide funding to promising investigators to encourage and promote quality research in clinical oncology. 5ASEAN Youth Award The ASEAN Youth Award recognises the outstanding contributions of ASEAN youth towards regional development and cooperation. The award is given to winners of National Youth Awards from the respective ASEAN countries for their active work in the field of youth development. 6NMRC – National Medical Research Council The NMRC Medical Research Fellowship/Scientist Award aims to provide doctors with the training necessary to become clinician scientists. This can include overseas research training or pursuing a PhD in research at a local institution.

The Clinician Scientist Investigator (CSI) / Clinician Scientist Award(CSA) Award aims to provide adequate salary & funding support for selected outstanding clinician scientists, who possess a consistent record of excellence in research, to enable them to carry out internationally competitive and influential translational and clinical research. The STaR Investigator Award is a prestigious award to recognise and support outstanding investigators in translational and clinical research. 7Unesco-L’Oreal for Women in Science International Fellowship Aims to promote and highlight the critical importance of ensuring greater participation of women in science. Each year, the programme recognises the achievements of exceptional female scientists across the globe and awards them with fellowships to help further their research. 8AACR

– American Association for Cancer Research The AACR Scholar-In-Training Award is open to medical students, graduate students and residents who wish to compete in the annual AACR abstract competition. Winners will be required to present their abstract at the AACR Annual Convention. 9SMF – Singapore Millennium Foundation The Scholarship / Post-Doctoral Scholarship Award is designed to promote and nurture R&D talent in areas of study that are of strategic importance to Singapore's economy and national development. 10SGH

– Singapore General Hospital The Annual Scientific Meeting provides the opportunity for the young clinicians, researchers, academicians, nurses and allied health staff in Outram Campus and Dukes-NUS GMS to interact and present their work.

11National

Research Foundation – Ministry of Health Healthcare Research Scholarship The scholarship provides support to Advanced Specialty Trainee (AST) doctors who wish to enrol in a PhD programme locally or overseas. It is targeted at clinicians intending to pursue a career in research.

12 The Singapore Science and Engineering Fair (SSEF) is intended for students who have conducted research over the past year to showcase their findings. Awards are given out to recognise the outstanding work produced by the students. 13 National Youth Council - Singapore Youth Award, Science and Technology This award is given out to honour youths in Singapore who have significantly achieved excellence and contributed to the society. 14Chinese

Government National Award for Outstanding Self-Financed Students Abroad The China Scholarship Council gives these awards annually to recognize the academic merit and research accomplishments of exceptional, self-financed students from China who are pursuing doctoral degrees in foreign countries.

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NEW APPOINTMENTS

Dr Alexandra PIETERSEN Senior Scientist PhD ncmap@nccs.com.sg

National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Alexandra Pietersen received her PhD from Erasmus University for investigating the use of gene therapy to induce tumour-specific apoptosis. Following postdoctoral work on cell fate decisions in the haematopoietic system at Utrecht University Medical Centre, she became a senior postdoc with Maarten van Lohuizen at the Netherlands Cancer Institute. There she investigated the epigenetic regulation of mammary stem cells and its link to breast cancer. In July 2008, she started her Laboratory of Mammary Gland Biology in the division of Cellular and Molecular Research at the National Cancer Centre Singapore, in affiliation with the Cancer and Stem Cell Biology programme at Duke-NUS Graduate Medical School. She holds an adjunct Assistant Professor position with the department of Physiology of the National University Singapore.

Originally from Lithuania, Gediminas Greicius performed graduate studies in the field of B lymphocyte biology at Karolinska Institutet, CMB and Stockholm University, Sweden, at the laboratory of Prof Eva Severinson. Thereafter, he joined Prof Sven Pettersson’s laboratory at Karolinska Institutet, MTC where he was involved in studies of cancerogenesis in APCmin+/ mice, a model of colorectal carcinoma. Currently, Gediminas Greicius is a Visiting Senior Scientist at the Laboratory of Inflammation Biology in National Cancer Centre Singapore. Host-microbe interaction in cancer models is the main area of his interest.

Dr Gediminas GREICIUS Visiting Senior Scientist PhD ncmgg@nccs.com.sg

Originally from Canada, Dr. Patrick Reilly performed his graduate research on viral-host cell interactions in Dr. Winship Herr's lab at the Cold Spring Harbor Laboratory. He later joined Dr. Tak Mak's laboratory at the Campbell Family Institute for Breast Cancer Research, where he developed numerous animal models for studies of cancer biology. He was also pivotal in scientific mentoring of several graduate students within the lab.

Dr Patrick REILLY Senior Scientist PhD ncmpr@nccs.com.sg

He continues his interest in mouse genetic models of cancer as a Senior Scientist within the Laboratory of Inflammation Biology.

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NEW APPOINTMENTS

Prof TEH Bin Tean MD, PhD Principal Investigator Teh.B.T@nccs.com.sg

Prof Sven PETTERSSON Principal Investigator MD, PhD Sven.Pettersson@ki.se

Professor Bin Tean Teh obtained his medical degree (1992) from the University of Queensland, Australia and his Ph.D. (1997) from the Karolinska Institute, Sweden. Following postdoctoral work in multiple endocrine neoplasia at Karolinska Institute, Dr. Teh joined the Van Andel Research Institute (VARI) as a Senior Scientific Investigator in the Laboratory of Cancer Genetics since January 2000. He is currently a Professor at the Duke-NUS Graduate Medical School, Singapore and serves as the Group Director for Translational Research at SingHealth. He also holds Adjunct Professorships in Universities/Institutes in Sweden, USA, and China. He also co-directs the Kidney Cancer Research Program at the Van Andel Research Institute in the USA. Additionally, Dr. Teh has published extensively in over 260 publications in high impact scientific journals and also sits on various Editorial Boards such as Lancet Oncology, Cancer Research, International Journal of Oncology, the Journal of Endocrine Genetics, the Journal of Clinical Endocrinology and Metabolism, Clinical Genitourinary Cancer, and the American Journal of Translational Research. Prof Pettersson received his PhD in 1985, MD from Ume책 University in Sweden in 1986. After his postdoc training in Cambridge, UK, he was recruited to Karolinska Institutet (KI) in 1991.Since 2001 he holds a strategic professorship in the field of host-microbe interactions at KI. His research aims to understand how normal commensal flora modulates host physiology. During his scientific career, Prof Pettersson has made many pioneering contributions in the field of genetics, immunology and recently also in neurobiology His publication list is extensive and he has co-authored some 130 publications. He is a cofounder of a small drug company, Index Ltd, in Sweden which has its first drug against colitis in a phase III trial. For this discovery, he was awarded an Astra-Zeneca prize for novel discoveries in 1996. He is also the Director for Germ-Free research at KI.

Prof Mak holds the distinction of being the first scientist to clone the genes of the human T-cell receptor in 1984. During his scientific career, he has made many pioneering contributions in the genetics of immunology. In 2004, he took on the position of Director at the Campbell Family Institute for Breast Cancer Research with a focus on breast cancer research. Also a University Professor at the University of Toronto, he co-authored over 500 scientific papers which have been published in top international scientific journals.

Prof TAK Wah Mak Principal Investigator PhD tmak@uhnresearch.ca

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For his contributions to medicine, Prof Mak has garnered numerous accolades such as the Emil von Behring Prize, Paul Ehrlich Prize, King Faisal Prize for Medicine and Sloan Prize of the General Motors Cancer Foundation, among others.


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

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Integrate basic, clinical and translational research aimed at the prevention, diagnosis and treatment of human cancers


Division of

Cellular and Molecular Research


BEK CHAI HEAH LABORATORY OF CANCER GENOMICS

Revolutionising Cancer Treatment through Personalised and Targeted Therapies Cancer arises from the accumulation of genetic changes. In our laboratory, we have focused on studying human hepatocellular carcinoma (HCC). To accelerate our effort to identify the molecular and genetic basis of HCC, we systematically study the expression of genes which expression is specifically altered. The availability of these “gene expression molecular maps” would indirectly inform us the genomic changes associated with these cancers and thus enable the identification of novel cancer-specific biomarkers and the design of novel therapeutic strategies.

Gene expression profiling between normal and cancerous tissues provides an unprecedented opportunity to identify holistically the biological pathways and processes that mediate carcinogenesis. The ability to determine which biological pathways are associated with differentially expressed genes form an unbiased way to gain an understanding of the molecular processes affected by the gene expression changes. The overall goal of our laboratory is therefore to interpret comprehensive gene expression changes in the context of underlying biological pathways and processes to identify the molecular pathways and processes affected upon carcinogenesis to enable the development of therapeutic strategies. Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for between 85% and 90% of primary liver cancers. HCC is one of the globe’s most common types of cancer and one of the most fatal. It is an epithelial cancer originating from hepatocytes and has been postulated to result from a series of genetic alterations attributable to a diverse range of causes. HCC has several distinctive epidemiologic features. Its worldwide prevalence varies widely and mirrors closely the geographical distribution of chronic viral hepatitis, its most important etiological agent. Surgery is currently the standard-of-care in the management of HCC and remains the only modality of treatment that most consistently prolongs patient survival. Patients with early stage category tumours may be effectively treated with surgical resection, transplantation, or percutaneous ablation. The 5-year survival rate can exceed 50%. However, currently available biomarkers for the detection of HCC are both non-specific and insensitive and there is considerable overlap between patients with chronic viral hepatitis and frank HCC. As a consequence, less than 20% of patients with HCC are amenable to surgery at the time of diagnosis and the overall prognosis of patients with inoperable HCC is dismal. Hence, there is an urgent and compelling need to identify biomarkers that could provide the early detection of HCC when the disease is most treatable, and to identify new molecular therapeutic targets that can be potentially developed into more efficacious treatment modalities.

Kam Man HUI Principal Investigator & Head, Division of Cellular & Molecular Research PhD (Northwestern), FRCPath (UK) cmrhkm@nccs.com.sg

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Research Staff Zhao Hui LI (PhD) Tina H T ONG (PhD) Rui ZHOU (PhD) Amudha DEVIASIGAMANI Jie GAO Derrick T H LOW Baskaran s/o NARAYANAN Feng SUN Hong Ping XIA


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

New technologies such as gene expression profiling are indispensable for further elucidation of the molecular events underlying hepatocarcinogenesis and enable the concurrent identification of potentially novel liver-specific therapeutic targets and/or specific transcriptional regulators to be incorporated into strategies to control the growth of HCC. One of our research focuses is to identify novel HCC-specific diagnostic and prognostic biomarkers through comprehensive gene expression profiling of normal and cancerous liver tissues. New molecular biomarkers with high sensitivity and specificity could eventually be made available for the early diagnosis of HCC. The challenge, however, remains in being able to validate these novel molecular therapeutic targets through clinical validations as efficacious therapies for HCC, both when HCC is inoperable and as adjuvant therapy in operated cases to significantly improve survival. We believe the early detection of HCC, when it is most treatable, is essential. The molecular function of some of these newly identified HCC-specific biomarkers are being studied in our laboratory.

Selected Publications Subramaniam K, Ooi LL, Hui KM Transcriptional down-regulation of IGFBP3 in human hepatocellular carcinoma cells is mediated by the binding of TIA-1 to its AT-rich element in the 3'-untranslated region. Cancer Lett. (2010) 297(2):259-68. Hui KM Human Hepatocellular Carcinoma: Expression Profiles-based Molecular Interpretations and Clinical Applications. Cancer Lett. (2009) 286(1):96-102. Puan KJ, Low JS, Tan TW, Wee JT, Tan EH, Fong KW, Chua ET, Jin C, Giner JL, Morita CT, Goh CH, Hui KM Phenotypic and functional alterations of V 2V 2 cell subsets in patients with active nasopharyngeal carcinoma. Cancer Immunol. Immunother. (2009) 58(7):1095-1107. Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. Exp. Biol. Med. (Maywood) (2009) 234(6):693-702.

Figure 1: Chromosomal localization of the 101 human HCC-specific genes identified by comprehensive gene profiling experiments.

Linn YC, Lau SK, Liu BH, Ng LH, Yong HX and Hui KM Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology (2009) 126:423-435. Liu BH, Goh CH, Ooi LL, Hui KM Identification of unique and common low abundance tumour-specific transcripts by suppression subtractive hybridization and oligonucleotide probe array analysis. Oncogene (2008) 27(29):4128-36.

Figure 2: Ability to segregate blood samples from HCC and normal patients by HCCgene signature derived in our laboratory.

Wang SM, Ooi LL, Hui KM Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin. Cancer Res. (2007) 13(21):62756283. Tan K, Cheang P, Ho AW Ivy, Lam YP Paula and Hui KM Nano-sized bio-ceramic particles could function as efficient gene delivery vehicles with target specificity for the spleen. Gene Therapy (2007) 14:828-835. Lau WM, Ho TH, Hui KM p16INK4A-silencing augments DNA damageinduced apoptosis in cervical cancer cells. Oncogene (2007) 26:6050-6060.

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LABORATORY OF MOLECULAR ENDOCRINOLOGY Novel Therapeutic Approaches for Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm accounting for approximately 667,000 worldwide cases annually. To improve our current therapies and to identify novel treatment for HCC, our laboratory has developed the models of HCC from patient’s tumour specimens. In this model, intact fragments of human HCC taken from patients are implanted into the liver of immuno-deficient mices. We have successfully used these tumour models as tools to identify effective therapies for patients.

National Xenograft Therapeutic Programs (NXTP): Translational platforms for preclinical and clinical studies in hepatocellular carcinoma Discovery-driven translational research in HCC is moving steadily from the study of xenograft models derived from established cell lines towards patient-derived xenograft models. To identify effective therapies, we have successfully developed patient-derived HCC mouse model xenografts. They have proven to be an indispensable asset in drug discovery, especially in targeted and combined therapies. Our group has profiled the protein expression of the primary tumours and comparison with corresponding xenografts show striking resemblance in the protein profile between the two. With the support from Singapore Cancer Syndicate, our group established the National Xenograft Therapeutic Program (NXTP) for HCC in 2006. NXTP is fast becoming a recognised industry and academic leader in the area of HCC drug development. Scientists from various pharmaceutical and biotechnology firms including AstraZeneca, Eli Lilly, Bristol Myers Squibb, GlaxoSmithKline, Novartis, and Roche have collaborated with our laboratory to provide their newly developed drugs to test on our xenograft models. As a direct result of our collaboration, AstraZeneca has signed an alliance with National Cancer Centre Singapore and other Singapore institutions both on a pre-clinical and clinical level. Recently, a joint research project between our laboratory and Roche has been established. This pre-clinical translational programme aims to study the in vivo mechanisms underlying Avastin action and Avastin-resistance in HCC and gastric cancer tumour models. Besides collaborations with pharmaceutical industries, we are working closely with a team of dedicated clinical scientists in NCCS who are enthusiastic about bench-to-bedside research and are committed to translating our laboratory findings onto clinical setting. Our clinical group (Dr Choo Su Pin, PI) designed a Phase I Study of Rapamycin in combination with Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma. From preclinical work on tumour vasculature to the mTOR signaling pathway in our laboratory, this clinical trial has provided novel molecular, cellular, and functional insights on tumour angiogenesis of HCC. We just completed the Phase I study and demonstrated the combination of bevacizumab with rapamycin showed promise for realistic benefit in patients enrolled in this trial. A Phase II Study of RAD001 in combination with Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma will start in early 2010. We recently reported that inhibition of the MEK/ERK pathway enhanced the antitumour effect of sorafenib in both orthotopic and ectopic models of HCC. These findings led to a Phase I/II study of sorafenib in combination with AZD6244 in advanced hepatocellular carcinoma, which started in January 2010.

The Hung HUYNH Principal Investigator cmrhth@nccs.com.sg Joint Appointments: Adjunct Professor, McGill University, Canada Adjunct Associate Professor, National University of Singapore > 20

Research Staff Valerie CHONG Chun Tzen JONG Irene W.L. LAM Swee Shean LEE

Tuan D.A. LUU Richard ONG Weng Hua KHOO Yang SHU


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Selected Publications Huynh H AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human HCC. Cancer (2010) 116(5):1315-25. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC AZD6422 (ARRY-142886) enhances the antitumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol. (2010) 52:79-87. Figure 1: Schematic showing how orthotopic models of human hepatocellular carcinoma (HCC) are created from primary HCC tumours. The human HCC tumours are grown in the livers of the mice and are parallel transplanted. Mice bearing human HCC tumours are used to identify the most effective therapies for the individual patients (individualised therapy) and to evaluate the efficacy of novel or existing drugs prior to clinical trials.

RESEARCH OUTCOMES: CLINICAL TRIALS (1)

Co-Principal Investigator (PI: Dr. Choo Su Pin). A Phase I Study of Rapamycin in combination with Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma (Completed)

(2)

Co-principal Investigator: A Phase II Study of RAD001 in combination with Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma (Started in 2010).

(3)

Co-Principal Investigator: Phase I/II study of sorafenib in combination with AZD6244 in advanced hepatocellular carcinoma (Started in January 2010)

Huynh H Tyrosine kinase inhibitors to treat liver cancer. Expert Opin. Emerging Drugs (2010) 15:1-14. Huynh H, Ngo VC, Choo SP, Poon D, Koong HN, Thng CH, Zheng L, Ong LC, Jin Y, Ong HS, Chung A, Chow P, Chang A, Soo KC Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular Carcinoma. Current Cancer Drug Targets (2010) 9:738-747. Huynh H, Fargnoli J Brivanib Alaninate. Drugs of the Future. (2009) 34:881-895. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell. Mole. Med. (2009) 13(8B):267383. Yang S, Ngo VC, Lew GB, Chong LW, Lee SS, Ong RWJ, Lam WLI, Thng CH, Koong HN, Ong HS, Chung A, Chow P, Lee J, Soo KC, Huynh H AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. Mol. Cancer Ther. (2009) 8(9):2537-2545. H Huynh, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow PK, Pollock P, Byron S, Tran E Brivanib (BMS-582664), a dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin. Cancer Res. (2008) 14:6146-6153. Huynh H, Palanisamy N, Salto-Tellez M, Goh BC, Lee CK, Somani A, Lee HS, Kalpana R, Yu K, Tan PH, Wu J, Soong R, Lee MH, Hor H, Soo KC, Toh HC, Chow PK, Tan P Effective inhibition of tumor growth in patient-derived xenografts of hepatocellular carcinoma by rapamycin and bevacizumab. J Hepatol. (2008) 49:52-60.

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LABORATORY OF CANCER GENE THERAPY

The main focus in our laboratory is to develop an ideal carrier or gene vector for the delivery of therapeutic agents into human cancer cells. Conventional cancer therapy has its limitations; surgery may not be the most appropriate treatment especially for tumours that are inaccessible, on the other hand, radiotherapy and chemotherapy are known to kill normal proliferating cells in addition to the cancer cells. As a result, patients often suffer from unpleasant side effects. Thus, one of our research objectives is to develop novel delivery vectors or carriers to complement the conventional therapy.

We are interested in the development of viral vectors, in particular, the Herpes Simplex Virus type 1 (HSV-1) amplicon viral vectors for gene therapy purposes. The advantages of these vectors include the ability to infect a broad range of mammalian cells, large DNA insert capacity up to 150kb, with minimal cytotoxicity due to the lack of helper viruses during the viral packaging process. Cancer is characterised by uncontrolled cellular proliferation. We capitalised on this unique property of cancer cells to develop a strategy whereby the transcription of the therapeutic gene is only activated in rapidly proliferating cells. The specificity of the vector is improved with the aid of cell-type specific promoter and/or glial-specific peptide incorporated into the viral-envelope coat. Furthermore, the therapeutic gene is fused with the luciferase reporter gene to better study the regulation and functionality of these viral vectors in mice bearing fluorescent proteins expressing tumour cells so as to demarcate the tumour boundary with clarity. This improvement has enabled us to understand how therapeutic modalities are activated in vivo, and significantly contributed to the overall design of the therapy regimens. Human mesenchymal stem cells (MSC) have generated a great deal of excitement as a potential source of cells for cellbased therapeutic strategies. In general, MSC appear to be a non-immunogenic population of cells and exhibit a unique property of tumour tropisms. One of our interests is to use the MSC as a carrier to deliver therapeutic agents especially to disseminated tumour cells. We are the first group to show that MSC can be readily infected by the HSV-1 amplicon viral vectors with no alterations in the intrinsic properties of the cells. This finding has led to the award of a travel fellowship to the EMBO International Cancer Conference 2005 and a Postdoctoral Fellowship from the Singapore Millennium Foundation.

Paula Y.P. LAM Principal Investigator PhD cmrlyp@nccs.com.sg Joint Appointments: Associate Professor, NUS Associate Professor, DukeNUS Graduate Medical School

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Research Staff Ivy AW HO (PhD) Tin Lum LAM (PhD) Berwini B ENDAYA Jennifer P NEWMAN Kian Chuan SIA YULYANA


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Systemic delivery of MSC circumvents problems associated with sitespecific delivery, such as calcification and tissue damage. However, during systemic application, MSC must transmigrate across the endothelium to exit the blood circulation, and subsequently invade their target tissues. In the process of unraveling the signaling cues to MSC migration, we show that the matrix metalloproteinase-1 (MMP1) is a key regulator of the tumourhoming property exhibited by the MSC. Targeted knockdown of MMP1 abolished the migration ability of the MSC, while overexpression of MMP1 in poorly migrating cells restored the defects. Apart from dissecting the molecular pathway to MSC migration, we are also keen to better understand the potential cross-talks between MSC and the tumour cells in an attempt to weigh out the pros and cons of using MSC to treat human cancers.

Selected Publications Sia KC, Chong WK, Ho IA, Yulyana Y, Endaya B, H Huynh and Lam PY Hybrid HSV/EBV amplicon viral vectors confer higher transgene expression in primary human tumors and human bonemarrow-derived mesenchymal stem cells. J. Gene Medicine (2010) 12(10):848-58. Ho IA, Ng WH, Lam PY FasL and FADD delivery by a gliomaspecific and cell cycle-dependent HSV-1 amplicon virus enhanced apoptosis in primary human brain tumors. Molecular Cancer (2010) 9:270. Ho IA, Hui KM, Lam PY Isolation of peptide ligands that interact specifically with human glioma cells. Peptides (2010) 31(4):644-650. Ho IA, Miao L, Sia KC, Wang GY, Hui KM, Lam PY Targeting human glioma cells using HSV1 amplicon peptide display vector. Gene Therapy (2010) 17(2):250-260. Ho IA, Chan KY, Ng WH, Guo CM, Hui KM, Cheang P, Lam PY Matrix metalloproteinase 1 is necessary for the migration of human bone marrowderived mesenchymal stem cells. Stem Cells (2009) 27(6):1366-1375. Ho IA, Chan KY, Miao L, Shim WS, Guo CM, Cheang P, Hui KM, Lam PY HSV-1 amplicon vector mediated gene transfer to human bone marrow-derived mesenchymal stem cells. Cancer Gene Therapy (2008) 15(9):553-562.

Figure 1: Human bone marrow-derived mesenchymal stem cell (blue or fluorescent red), when injected into the contralateral hemisphere, migrate toward brain tumour cells (green).

Lam PY, Sia KC, Khong JH, De Geest B, Lim KS, Ho IA, Wang GY, Miao LV, Huynh H, Hui KM An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas. Mol Ther. (2007) 15(6):1129-36. Sia KC, Wang GY, Ho IA, Khor HY, Miao L, Hui KM, Lam PY Optimal purification method for herpesbased viral vectors that confers minimal cytotoxicity for systemic route of vector administration. Journal of Virological Methods (2007) 139(2):166-174. Wang GY, Ho IA, Sia KC, Miao L, Hui KM, Lam PY Engineering of an improved cell cycle regulatable HSV-1 amplicon vector with enhanced transgene expression in proliferating cells yet attenuated activities in resting cells. Human Gene Therapy (2007) 18(3):222231. Ho IA, Hui KM, Lam PY Targeting proliferating tumor cells via the transcriptional control of therapeutic genes. Cancer Gene Therapy (2006) 13(1):4452. Lam PY, Lim KS, Wang SM and Hui KM Apoptosis induced by TIMP-3 in glioma cells. Molecular Therapy (2005) 11(7):144-152.

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LABORATORY OF INFLAMMATION BIOLOGY

The role of the immune system in cancer is far more complex than originally imagined. It is increasingly accepted that chronic inflammation can advance local tumour growth. Our research sets out to examine the role of inflammation in cancer by combining cutting-edge imaging technique and novel mouse models.

Our research uses animal models of colorectal cancer (CRC) as a foundation for investigating inflammatory initiation and signaling. Inflammation in the colon is very tightly regulated in light of the myriad of microbes that are constantly exposed to the gut epithelia. Most of these microbes are bacteria that are co-evolved with mammals to improve the health of the host. A small minority, however, can be pathogenic and can cause or aggravate inflammatory bowel disorders (IBD). Through various lines of evidence, we now know that gut bacteria are also able to accelerate CRC progression, most likely through these same inflammatory processes.

Identifying Specific Pathogenic Bacteria in CRC The identification of the bacteria Helicobacter pylori as the causative agent in stomach cancer has enlightened the scientific community on the possibility that certain strains of bacteria could also be responsible for enhancing CRC. One of our overall aims is to identify such bacteria and understand how they might function in disease progression. We are now testing clinical isolates of bacteremia cases from CRC see their effects on inflammation in vitro as well as intestinal cancer progression in vivo.

Tak Wah MAK Principal Investigator PhD tmak@uhnresearch.ca Joint Appointment: Professor, University of Toronto Director, Campbell Family Inst. of Breast Cancer Research Sven PETTERSSON Principal Investigator MD, PhD Sven.Pettersson@ki.se Joint Appointment: Professor, Karolinska Institute Group Leader, Genome Institute of Singapore

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Research Staff Gediminas GRECIUS (PhD) Patrick REILLY (PhD) Shih Wee SEOW (PhD)


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Genetic influences on inflammation response

Selected Publications

The outcome for individuals in response to an environmental cue will commonly be different based on their genetic diversity. This is almost certainly true of inflammatory processes in tumourigenesis. Thus, by identifying and testing disease-related genes we can get greater understanding on the best therapeutic strategies. To this end, we have focused on the genetics of patients with IBD and other chronic inflammatory disorders. Using cutting-edge genomic techniques we have identified numerous candidate genes for testing in animal models. One gene of particular focus is the anti-inflammatory Aryl hydrocarbon receptor (AhR). We are currently investigating the detailed mechanism by which AhR responds to small molecule messages to suppress inflammation in IBD and cancer.

Reilly PT, Afzal S, Wakeham A, You-Ten A, Haight J, Zaugg K, Dembowy J, Young A, and Mak TW Generation and characterization of the Anp32e-deficient mouse. PLoS One (2010) 5(10):e13597.

Improved platforms for studying inflammation in CRC Although CRC is a common type of cancer both in Singapore and throughout the world, it can be difficult to study in animal models. For one thing, the influence of gut microbiota on the disease means that there is inconsistency among different laboratories. For analysing the bacterial contribution to diseases as well as normal development, we have initiated a germ-free animal colony within SGH, the first of its kind in South-East Asia. Using this germfree environment, we can analyse with high fidelity the contributions of either specified or general microbes in an array of physiological activities. Another major drawback to our understanding of CRC is our limited capacity to track the disease over time to determine the dynamics of different interventions. To this end, we are generating several potential models for fluorescent and luminescent detection of early tumourigenesis. Such models will be valuable additions to the scientific community where in vivo detection of disease is becoming a critical tool in testing the actions of environmental factors.

McIlwain DR, Pan Q, Reilly PT, Elia AJ, McCracken S, Wakeham AC, ItieYouten A, Blencowe BJ, Mak TW Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay. Proc. Natl. Acad. Sci. USA (2010) 107(27):12186-91. McGovern DP et al. Genome-wide association identifies ,ultiple ulcerative colitis susceptibility loci. Nature Genetics (2010) 42:332-7. Maria Genander, Michael M. Halford, Zuoren Yu, Anna Martling, Nan-Jie Xu, Gedas Greicius, Richard G. Pestell, Sven Pettersson, Mark Henkemeyer ,Jonas Frisén Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell (2009) 139:679-92. Britta Björkholm, Chek Mei Bok, Annelie Lundin, Joseph Rafter, Martin Lloyd Hibberd, Sven Pettersson The intestinal microbiota modulate xenobiotic metabolism physiology in the liver. PLoS ONE (2009) 9:4-10. Lechmann M, Shuman N, Wakeman A, Mak TW The CD83 reporter mouse elucidates the activity of the CD83 promotor in B, T and dendritic cell Populations in vivo. PNAS (2008) 105(33): 11887-92. Brü'fcstle A, Heink S, Huber M, Rosenplänter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat. Immunol. (2007) 8(9):958-66.

Figure 1: Imaging of small intestinal tumours in the mouse ileum. Red foci mark regions of cancer-associated cathepsin activity. Green staining displays immune-associated matrix metaloproteinase activity with green arrow displaying a Peyer’s Patch, an immune follicle of the intestinal tract.

Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, Pettersson S, Conway S Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPARgamma and RelA. Nat. Immunol. (2004) 5(1):104-12.

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LABORATORY OF MAMMARY GLAND BIOLOGY

Some tumour cells share characteristics with tissue stem cells, and it may be these properties that render tumour cells particularly difficult to kill. We study what mechanisms govern mammary stem cells and how their deregulation contributes to breast cancer.

Mammary stem cells and breast cancer Of all the cells in a tissue, stem cells seem to be especially sensitive to signals from their surroundings, therefore it is important to analyse these cells in vivo, e.g. in a mouse. The mouse mammary gland provides a unique model system to study epithelial stem cell biology because stem cell activity can be quantified in vivo, unlike tissues such as the intestine or the skin. In addition, we have the means to isolate breast stem cells based on their cell surface profile with a cell sorter, and subsequently alter genes in these cells to mimic what is observed in breast cancer. After transplanting these cells back into the mouse, we can study the effect on the behaviour of the stem cells and the cells they generate. The problem with studying cancer is that by the time a tumour is detected, so much has changed that it is difficult to determine what alterations were driving the tumorigenic process and which ones are a mere byproduct of uncontrolled growth. By approaching this question from the other side, i.e. by changing genes one by one in normal cells, we hope to gain a better understanding what changes are relevant and whether these changes could be targeted in specialised cancer therapy. My previous studies at the Netherlands Cancer Institute (NKI) demonstrated that a gene that is overactive in breast cancer and was thought to play a role in stem cells, called Bmi1, which in fact only had a minor role in breast stem cells. Importantly, our studies showed that women with too much Bmi1 in their breast tumour have a better chance of surviving, and it is Bmi1’s counterpart Ezh2 that correlates with stem cell characteristics and poor survival rates. At the moment, studies at NKI are carried out to test an inhibitor of Ezh2 (discovered by Yu Qiang at the Genome Institute Singapore) in mouse models of breast cancer. At the National Cancer Centre Singapore, we are currently focusing on two different classes of genes and their role in mammary stem cells and breast cancer: T-box repressors and the Wip1/p38 pathway.

Alexandra PIETERSEN Senior Scientist PhD ncmap@nccs.com.sg Joint Appointments: Assistant Professor, Duke-NUS Graduate Medical School Assistant Professor, Dept of Physiology, National University of Singapore

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Research Staff Gerard TARULLI (PHD) Duvini DE SILVA Kakaly GHOSH Jen Nee GOH Victor HO


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Tbx3 is important for embryonic stem cells, involved in the earliest stages of breast development and highly active in some breast cancers. By putting overactive Tbx3 into mammary stem cells and transplanting them back into the mouse, we hope to understand how Tbx3 affects the different cell types in the mammary gland and how it could contribute to breast cancer. Our collaborator at the Institute of Molecular and Cell Biology in Singapore, Dmitry Bulavin, recently demonstrated that Wip1 determines the sensitivity of stem cells in the intestine to radiation. Since Wip1 is overactive in 15% of human breast cancer, we are now studying whether Wip1 plays a similar role in mammary stem cells, and if targeting Wip1 could make radiotherapy against breast cancer more effective.

Selected Publications Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, Nederlof P, Yu Q, Jonkers J, van Lohuizen M, Pietersen AM BRCA1-deficient mammary tumors cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. (2009) 11(4):R63. Pietersen AM, Horlings HM, Hauptmann M, Langerø'f8d A, Ajouaou A, Cornelissen-Steijger P, Wessels LF, Jonkers J, Van de Vijver MJ, Van Lohuizen M Ezh2 and Bmi1 inversely correlate with prognosis and p53 mutation in breast cancer. Breast Cancer Research (2008) 10(6): R109. Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, Van Lohuizen M Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium. Current Biology (2008) 18(14):1094-9.

Figure 1: Mammary gland development is visualised by carmine staining. At the left, a small mammary tree is visible in the fatty breast tissue of a mouse before puberty (black oval is a lymph node). During puberty, the milk ducts fill the fat and grow beyond the lymph node.

Pietersen AM, Van Lohuizen M Stem cell regulation by Polycomb repressors: postponing commitment. Current Opinion in Cell Biology (2008) 20(2):201-207. Pietersen AM, Rutjes SA, van Tongeren J, Vogels R, Wesseling JG, Noteborn MH The tumor-selective viral protein apoptin effectively kills human biliary tract cancer cells. J. Mol. Med. (2004) 82(1):56-63.

Figure 2: Analysis of cell identity in breast tissue using fluorescently labeled markers. Left picture is a section through a normal mammary milk duct, right picture shows an early stage of a mouse breast tumour.

Van der Eb MM, Pietersen AM, Speetjens FM, Kuppen PJK, Van de Velde CJH, Noteborn MHM, Hoeben RC Gene Therapy with Apoptin induces regression of xenografted human hepatomas. Cancer Gene Therapy (2002) 9(1):53-61. Pietersen AM, Van der Eb MM, Rademaker HJ, Van den Wollenberg DJM, Rabelink MJWE, Kuppen PJK, Van Dierendonck JH, Van Ormondt H, Masman D, Van de Velde CJH, Van der Eb AJ, Hoeben RC, Noteborn MHM Specific tumor-cell killing with adenovirus vectors containing the Apoptin gene. Gene Therapy 1999 6(5):882-892.

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LABORATORY OF MOLECULAR CARCINOGENESIS

Tumour formation is a multi-step process involving the deregulation of specific genes and the pathways they control in regulating cell growth and cell death. These genetic changes confer a selective growth or survival advantage to the mutant cells that no longer respond to normal regulatory signals, as well as to therapeutic agents, and grow in an uncontrolled manner, resulting in malignant disease. The goal of our research is thus to understand the cause and nature of these changes so that efficient molecular-based therapeutic strategies can be developed to eradicate cancerous cells.

The molecular basis of carcinogenesis and therapeutic resistance The focus of the laboratory is to understand the molecular mechanisms contributing to carcinogenesis – the process of cancer formation, and the alterations that lead to therapeutic resistance, with the aim of finding ways to combat cancer and enhance treatment response. As cells are constantly exposed to a variety of signals including growth promoting factors and detrimental stresses, cell fate determinations have to be constantly and correctly made such that an appropriate response ensues. Defects in signaling mechanisms will inadvertently lead to altered cell fate responses resulting in both altered physiological processes and the development of pathological conditions such as cancer. The determination of cell fate is a tightly orchestrated process regulated by the interplay of various cellular signaling cascades. Prominent among them is the proto-oncogene cJun, a member of the AP-1 family of transcription factors, and the tumour-suppressors p53 and p73. All 3 gene-products are transcription factors involved in regulating gene expression, and hence, have the ability to turn on the appropriate target genes for cell fate determination. Alterations in p53 are one of the most frequent occurrences in cellular transformation, and hence, p53 is not functional in more than 50% of ALL human cancers, indicating its critical role in maintaining a cancer-free environment in the organism. In normal cells, p53 regulates cell growth by controlling cell proliferation and cell death. Mutations in p53 lead to the loss of these growth suppressive functions, and have also been thought to provide novel growth promoting gain-of-functions, thus leading to uncontrolled growth. We are therefore investigating the specific roles of mutant p53, not only in leading to cancer formation, but also in preventing proper therapeutic response, with specific focus on hepatocelluar carcinoma (figure 1). Figure 1: Genetically engineered mouse models to study hepatocellular carcinoma (HCC) formation and role of p53.

Kanaga SABAPATHY Principal Investigator PhD cmrksb@nccs.com.sg

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Research Staff Wilawan BUNJOBPOL (PhD) Iqbal DULLOO (PhD) Kenneth M.K. LEE (PhD) Anbalagan MOORTHY (PhD) Deepa SUBRAMANIUM (PhD) Rami SUKRIEH (PhD)

Eric ALLEN Amy H.W. CHUA Shin Yuen NAM Beng Hooi PHANG Wei Wei TEOH Min XIE


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Unlike p53, its relative and homologue, the p73 tumour suppressor gene, is not mutated but over-expressed in many cancers. The cause and consequence of overexpression of p73 is at present unclear. Evidence indicate that p73 overexpression can lead to chemoresistance. In addition, we have recently shown that p73 overexpression is capable of promoting cellular survival as well, in defined cellular contexts (figure 2). Thus, we are focusing on understanding the role and regulation of p73, particularly with reference to its ability to induce both cell death and promote survival. Activation of the proto-oncogene gene product, c-Jun, has been shown to induce both cell death and proliferation. How c-Jun executes such opposite cellular effects is still enigmatic. Importantly, its activity is elevated in cancers, raising the possibility that it can affect cancer development and therapeutic response. Thus, we are trying to understand how c-Jun cooperates with various co-activators in bringing about these diverse effects, such that we can find ways to skew the decision favorable to the inhibition of cancer development and to enhance response. Eventually, it is hoped that the knowledge gained through such studies will allow the identification of suitable targets for therapy and the design of better approaches to treat cancer.

Selected Publications Lee MK, Tong WN, Wang ZQ, Sabapathy K Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo. Cell Death & Diffn. (2010) Epub ahead of print. DullooD, Gopalan G, Melino G, Sabapathy K The anti-apoptotic DeltaNp73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizymemediated pathway. PNAS. (2010) 107(11):4902-7. Toh WH, Nam SY, Sabapathy K An essential role for p73 in regulating mitotic cell death. Cell Death & Diffn . (2010) 17(5):787800. Lee MK, Sabapathy K The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo. J. Cell Science (2008) 121:1899-906. Lum SS, Chua HW, Li H, Li WF, Rao N, Wei J, Shao Z, Sabapathy K MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onsetage of sporadic breast cancers in the Chinese population. Carcinogenesis (2008) 29(4):754-61. Toh WH, Logette E, Corcos L, Sabapathy K TAp73 and DNp73 activate the expression of the pro-survival caspase-2S. Nucleic Acids Res. (2008) 36(13):4498509.

Figure 2: p73 overexpression in cancers - evidence for promotion of cellular growth and survival.

Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH, Vousden KH, Sabapathy K p73 supports cellular growth through cJun-dependent AP-1 transactivation. Nature Cell Biol. (2007) 9(6):698-705. Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, Sabapathy K c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ. (2007) 14(2):218-29. Vikhanskaya F, Siddique MM, Broggini M, Sabapathy K Evaluation of the combined effect of p53 codon 72 polymorphism and hot-spot mutations in response to anticancer drugs. Clin. Cancer Res. (2005) 11:4348-56. Toh WH, Kyo S, Sabapathy K Relief of p53-mediated telomerase suppression by p73. J. Biol Chem. (2005) 280(17):17329-38. Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jundependent cell proliferation. Mol. Cell. (2004) 15(5):713-25.

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LABORATORY OF GENOMIC ONCOLOGY

Cancers between individual patients often display strikingly different types of clinical behaviour including disease aggressiveness and responses to treatment. Many of these differences are currently not predictable using conventional techniques for cancer classification, such as light microscopy and immunohistochemistry. Our laboratory employs genome-profiling technologies to identify molecular features of tumours that will enable such predictive classification, and to ultimately provide personalised cancer care.

Our group focuses on the application of genome-scale technologies to address biological questions in cancer. We are also intrigued by the rapid mutability and genetic plasticity of the cancer genome and believe that developing whole genome cartographies of tumours will enable us to better understand the molecular basis of cancer and to identify cellular pathways and molecular nodes for intervention. A major disease focus for our group is gastric cancer, which is the second leading cause of global cancer mortality. Despite this clinical importance, relatively little is known about the specific oncogenic pathways that regulate different aspects of the gastric cancer phenotype. We hope to identify and understand these pathways and ultimately use this knowledge to define rational therapeutic strategies for gastric cancer patients. For example, using a novel computational approach, we showed that gastric cancers can be subdivided into different subtypes with differing patterns of oncogenic pathway activity and clinical outcomes. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we formed an international Gastric Cancer Consortium comprising members from Australia, Hong Kong, Japan and Singapore, to pool expression data from more than 300 human samples profiled at various histological stages of gastric tumorigenesis, ranging from normal gastric tissue, chronic gastritis, intestinal metaplasia, to overt carcinoma. Using this combined database, we were able to show a conserved interaction between PLA2G2A, a gene whose expression was previously correlated with patient prognosis, and the EphB2 receptor, raising the possibility that signalling through this receptor may contribute to gastric carcinogenesis. We further extended this work to show that PLA2G2A is a novel target of the Wnt signalling pathway that functions to inhibit gastric cancer metastatasis.

Patrick TAN Adjunct Principal Investigator MD, PhD cmrtan@nccs.com.sg Joint Appointments: Associate Professor, DukeNUS Graduate Medical School Group Leader, Genome Institute of Singapore Program Leader (Genomic Oncology), Cancer Sciences Institute of Singapore

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Research Staff Nian Tao DENG Yujing LIU Qin LUO Hue Kian OH Chia Huey OOI Kalpana RAMNARAYANAN Angie L.K. TAN Iain Bee Huat TAN Jiong TAO Hannah Z.A. WANG Jeanie WU Yonghui WU Shenli ZHANG Zhijiang ZHANG Yansong ZHU Hermioni ZOURIDIS


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

In addition to our focus on gastric cancer, we have also actively participated in numerous projects involving lung, liver, and breast cancers.

Selected Publications Ooi CH, Ivanova T, Wu J, Lee M, Tan B Iain, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim D, Chan WH, Wong WK, Bowtell B, Yeoh KG, Grabsch H, Boussioutas A, and Tan P Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer. PLoS Genet. (2009) 5(10):e1000676. Yu K, Ganesan K, Tan LK, Laban M, Wu J, Zhao XD, Li H, Zhu Y, Wei CL, Hooi SC, Miller L, Tan P A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers. PLoS Genet. (2008) 4(7): e1000129.

Figure 1: Systems-Map of Gastric Cancer – Each circle represents a collection of genes that are tightly co-regulated across more than 300 gastric tissues. For more details see Aggarwal et al., (2006).

Hou Q, Wu YH, Grabsch H, Zhu Y, Leong SH, Ganesan K, Cross D, Tan LK, Tao J, Gopalakrishnan V, Tang BL, Kon OL, Tan P Integrative Genomics Identifies RAB23 as an Invasive Mediator Gene in Diffuse Gastric Cancer. Cancer Res. (2008) 68: 4623-4630. Ganesan K, Ivanova T, Wu YH, Rajasegaran V, Wu J, Lee MH, Yu K, Rha SY, Chung HC, Ylstra B, Meijer G, Kon OL, Grabsch H, Tan P Inhibition of Gastric Cancer Invasion and Metastas is by PLA2G2A, a Novel β catenin/TCF Target Gene. Cancer Res. (2008) 68(11):4277-4286. Aggarwal A, Guo DL, Hoshida Y, Yuen ST, Chu KM, So S, Boussioutas A, Chen X, Bowtell D, Aburatani H, Leung SY, Tan P Topological and Functional Discovery in a Gene Co-expression Meta-Network of Gastric Cancer. Cancer Res. (2006) 66, 232-241 (cited on journal cover).

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MOLECULAR RADIOBIOLOGY LABORATORY (GENOME MAINTENANCE/DNA REPAIR)

Research in our laboratory primarily focuses on undertaking a series of hypothesisdriven, mechanistic studies into various components of genome maintenance network (GMN). Cancer, at its very core, is a genetic disease with its molecular underpinnings traced to a group of genes coding for proteins that mediate cell cycle progression, DNA repair, programmed suicide (apoptosis) and the ‘upstream’ cell membrane signaling and transduction regulatory cascades. Collectively, these systems form a complex, interconnected homeostatic circuitry – denoted genome maintenance network (GMN) – that enables a human cell to sense and respond to different types of genotoxic stress (e.g. solar UV rays or toxic chemicals).

Deregulation of GMN, arising from mutations in the genes encoding key network-mediating proteins, constitutes a common thread in the origin of genomic instability. This is now widely held as the initiating and rate-limiting event in many forms of malignant growth. Human radiosensitive syndromes have also been linked to many genes that mediate the repair of various DNA lesions. Examples of these syndromes include Fanconi Anemia, Ataxia Telangiectasia, Nijmegen Breakage Syndrome, LIG4 syndrome and RS-SCID. The genes mutated in the latter syndromes are all involved in the response to and repair of DNA double strand breaks (DSBs). The primary focuses of research in our laboratory are on undertaking a series of hypothesis-driven, mechanistic studies into various components of GMN, which include follow-up investigations into our recent findings that: 1. ATM, the serine-threonine protein kinase mutated in the rare cancer-prone and radiotherapy-sensitive syndrome ataxia telangiectasia (A-T), operates as a molecular switch for integrating calcium signaling and stress-response pathways (e.g. S-phase checkpoint in which DNA replication is transiently arrested in response to -radiation); 2.

Treatment of cultured skin cells derived from A-T patients with the eicosanoid prostaglandin E2 (PGE2) corrects the inability of these ATM- deficient cells to undergo S-phase checkpoint after -irradiation. This surprising finding implies that PGE2 can act as an extracellular signaling molecule in -ray-damaged A-T cells, inducing DNA synthesis shutdown via an alternative, ATM-independent signal transduction pathway;

3. The SWI/SNF chromatin remodeling complexes are known to mediate the repair of DNA doublestrand breaks (DSB) in -irradiated human cells; similarly, activation of ATM protein kinase is crucial to efficient DSB repair and our preliminary data suggests that the SWI/SNF complexes interact closely with activated ATM in response to DSB, triggering multiple signaling cascades culminating in both DSB repair and checkpoint control to arrest cell cycle progression until repair processes have run their course;

Susan L. LOONG Associate Investigator FRCP (Edinburgh) FRCR (Clinical Oncology) MD (Edinburgh) trdlle@nccs.com.sg

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Research Staff Rajamanickam BASKAR (M.Sc., M.Phil., Ph.D.) Seow Fong YAP (PhD) Cynthia S.K. BOO (BSc)


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

4. Cell lines from adult cancer patients with untoward responses to standard courses of ionising radiation (IR) have impaired fast component of IR induced DNA DSBs (D-NHEJ) and this is associated in vitro with increased but error prone DNA end-joining. Since D-NHEJ is associated with the pathway of DNA-DSBs carried out by the DNA-PK heterotrimer complex, research is currently focused on the protein-protein interplay of the known interacting proteins.

DNA Damage

Selected Publications Wee JT, Ha TC, Loong SL, Qian CN Is nasopharyngeal cancer really a "Cantonese cancer"?. Chinese J. of Cancer (2010) 29(5): 51726. Baskar R Emerging role of radiation induced bystander effects: Cell communications and carcinogenesis. Genome Integrity (2010) 1(1):13. Gurung RL, Lim SN, Khaw AK, Soon JF, Shenoy K, Mohamed Ali S, Jayapal M, Sethu S, Baskar R, Hande MP Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. PLoS One (2010) 5(8):e12124.

DNA damage response pathways STOP

Cell Cycle Control

R.I.P

Apoptosis

Transcription

Figure 1: DNA Damage response pathways.

DNA Repair

Loong SL, Hwang JS, Li HH, Wee JT, Yap SP, Chua ML, Fong KW, Tan TW Weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01). Radiat. Oncol. (2009) 4:23. Baskar R, Hande MP A comparative study of protein kinase C activation in -irradiated proliferating and confluent human lung fibroblast cells. J. Radiat. Res. (2009) 50(5):415-23. Loong SL, Hwang JS, Lim ST, Yap SP, Tao M, Chong TW, Tan LH, Huynh H An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing. Leukemia Lymphoma (2008) 49(6):11617. Tan WM, Paterson MC, Koo GC, Li HH, Price A, Loong SL Increased but error-prone nonhomologous end joining in immortalized lymphoblastoid cell extracts from adult cancer patients with late radionecrosis. Int. J. Radiat. Oncol. Biol. Phys. (2008) 72(1):178-85. Baskar R, Moore PK Nuclear accumulation and up regulation of p53 and its associated proteins after H(2)S treatment in human lung fibroblasts. J. Cell. Mol. Med. (2008) 12: 2297-300. Baskar R, Balajee AS, Geard CR Isoform-specific activation of protein kinase c in irradiated human fibroblasts and their bystander cells. Int. J. Biochem. Cell Biol. (2008) 40(1):125-34. Baskar R, Sparatore A, Del Soldato P, Moore PK Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative inhibits rat vascular smooth muscle cell proliferation. Eur. J. Pharmacol. (2008) 594(1-3):1-8.

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The Division of Medical Sciences, through clinician-scientist networks, innovates new methods for patientcentred cancer diagnosis, treatment and prevention.


Division of

Medical Sciences


LABORATORY OF CLINICAL PHARMACOLOGY

The Clinical Pharmacology Laboratory is involved in (a) early phase I and II clinical trials, and (b) studying the causes and consequences of inherited variations in genes encoding drug-metabolising enzymes, drug transporters and drug targets. These are either investigator initiated studies or pharmaceutical industry initiated studies. There are often significant differences in the way drugs act in patients belonging to different ethnic populations and these observations may be due to the presence or absence of specific functional polymorphisms in genes involved in regulating the disposition of drugs. The primary objectives of our research activities are to identify the genetic causes of interindividual or interethnic variability in drug disposition and translating the basic pharmacogenetic findings into predictive information pertaining to patient response to drugs. The research approach in our lab includes pharmacokinetic, genetic, molecular biology and analytical techniques on humans, human tissues, animal models, cloned genes and expressed gene products to analyse drug disposition, gene structure, gene regulation, and allelic variations.

Clinical Pharmacology Studies (A) Pharmacogenetics of Irinotecan Irinotecan is a topoisomerase I inhibitor used in the treatment of colorectal cancer. It has a complex pharmacology involving the participation of several phase I and II drug metabolising enzymes as well as phase III drug transporters. Two main toxicities associated with the use of irinotecan include severe diarrhoea and neutropenia. The occurrence of these toxicities depends on the presence or absence of two polymorphic variants in the UGT1A1 gene, namely, UGT1A1*28 and UGT1A1*6. Our laboratory has characterised the influence of these UGT1A1 polymorphisms as well as other polymorphisms across the irinotecan biochemical pathway. Our findings have recently led to a local drug label change for irinotecan whereby dosage reduction is recommended in patients homozygous for the UGT1A1*28 or UGT1A1*6 allele. A prospective phase I study involving genotype-directed dosing of irinotecan is ongoing.

Balram CHOWBAY Principal Pharmacologist PhD ctebal@nccs.com.sg

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Research Staff Prathap BALASUBRAMANIAN Xiang Ai CHEN Subramaniyan KOILAN Anupama MAHAJAN Rathi RAMASAMY Saminathan RAMASAMY Onkar SINGH


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

(B) Doxorubicin-Cyclophosphamide (AC) Metabolism and Transport The combination of doxorubicin and cyclophosphamide is commonly used in the treatment of breast cancer. Both drugs have a very complex pharmacology and several drug enzymes and drug transporters are involved in influencing their pharmacokinetics. Side effects to these drugs may be due to altered drug disposition in cancer patients. Present research includes characterising the pharmacogenetic profile across the doxorubicin metabolic pathways with a focus on newly identified doxorubicin transporter proteins as well as an understanding of their impact on disposition of doxorubicin in breast cancer patients receiving adjuvant chemotherapy.

Core Research Activities: Pharmacokinetics: HPLC quantification of drugs metabolites, analysing ADME parameters and PK-modelling. Pharmacogenetics: DNA sequencing, SNP detection and genotyping, Real-time RTPCR, Taqman genotyping, High Resolution melting, miRNA profiling, and reportergene assay etc Pharmacoproteomics: Serum profiling, Biomarker discovery, Immunoblotting, Sandwich-ELISA etc Bioinformatics: Dosing models, Haplotype and Tag-SNP analysis, Genotype and phenotype correlation, Transcription factor binding analysis, pathway network analysis etc

Selected Publications Sandanaraj E, Lal S, Cheung YB, Xiang X, Kong MC, Lee LH, Ooi LL, Chowbay B VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients. Drug Metab. Pharmacokinet. (2009) 24(4):365-75. Zhou SF, Liu JP, Chowbay B Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab. Rev. (2009) 41(2):89-295.

(C) Tamoxifen pharmacogenetics Tamoxifen (TAM) is a selective estrogen receptor modulator drug that is widely used in the prevention and treatment of breast cancer. Genetic alterations in certain CYP-450 enzymes alter the conversion of tamoxifen into its most active form, endoxifen. Our laboratory is currently investigating the pharmacogenetics of tamoxifen in Asian breast cancer patients. (D) Pharmacogenetics of Taxanes Taxanes (paclitaxel or docetaxel) belong to a class of anti-mitotic chemotherapeutic agent. They are frequently used in the treatment of a wide variety of solid tumours such as breast, prostate, ovarian and lung, as well as less common malignancies of gastric, and head and neck. Our laboratory is interested in investigating the genetic variations in the genes encoding the drug metabolism enzymes and transporters across the taxane biochemical pathway, and their influence on the pharmacokinetics and pharmacodynamics of taxanes in Asian cancer patients. (E) Imatinib pharmacogenetics Imatinib is a tyrosine kinase inhibitor and acts by competitively inhibiting the ATP binding sites of tyrosine kinases in leukaemic cells. Recent data suggests that intracellular levels of imatinib are affected by the degree of SLC22A1 expression levels in leukaemic cells in CML patients. The expression levels of SLC22A1 may be influenced by functional SNPs in the SLC22A1 gene. Our laboratory is investigating the SNP profile of SLC22A1 gene as well as other genes across the imatinib biochemical pathway and their impact on the pharmacokinetics and pharmacodynamics of imatinib in Asian CML patients.

Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, Chowbay B CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. (2008) 99(10):2045-54. Wang XD, Deng XY, Chen J, Li JL, Chen X, Zhao LZ, Lu Y, Chowbay B, Su QB, Huang M, Zhou SF Single nucleotide polymorphisms of the pregnane x receptor gene in Han Chinese and a comparison with other ethnic populations. Pharmacology (2008) 81(4):350-4. Sandanaraj E, Selvarajan V, Lal S, Ooi LL, Wong ZW, Ang PC, Lee EJ, Chowbay B PXR Pharmacogenetics: Association of haplotypes with hepatic CYP3A4 and ABCB1 mRNA expression and doxorubicin clearance in Asian breast cancer patients. Clin. Cancer Res. (2008) 14(21):71167126. Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ, Chowbay B Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. (2008) 99(4):816-823. Sandanaraj E, Jada SR, Shu X, Lim R, Lee SC, Zhou Q, Zhou SF, Goh BC, Chowbay B Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients. Pharmacogenomics J. (2008) 8:174-185. > 37


LABORATORY OF ONCOPROTEOMICS

Gastric cancer is a significant public health burden, being the second leading cause of cancer-related deaths worldwide. Our laboratory aims to reduce gastric cancer mortality and to improve patient outcomes via (1) the discovery of sensitive and specific protein markers for early disease detection and (2) elucidate the mechanism of gastric oncogenesis so that molecularly-directed therapies can be developed to intercept cancer development and progression.

I. Biomarker Discovery in Gastric Cancer Using Proteomic Approaches While the incidence of gastric cancer is slowly declining in many developed countries, it is the leading cause of cancer deaths in many developing countries and in some East Asian countries such as China, Korea, and Japan. Globally, there are nearly one million new cases of gastric cancer diagnosed every year and more than 700,000 individuals die from this cancer annually. Its lethality is mainly due to the lack of reliable and clinically acceptable techniques for diagnosing early-stage gastric cancer (Figure 1). In addition, there are currently no biomarkers of acceptable sensitivity and specificity for gastric cancer. The prognosis for late-stage gastric cancers is poor owing to limited treatment options. But when it is detected early, the 5-year survival for gastric cancer patients exceeds 90%. Thus, we believe that one of the key strategies to reduce gastric cancer mortality and to improve patient outcomes lies in the discovery of highly specific and sensitive biomarkers for early disease detection. Informative biomarkers will aid diagnosis and ensure early clinical intervention, thereby preventing mortality and reducing morbidity.

Figure 1. Examples of advanced gastric carcinoma.

Proteomics is a rapidly emerging field in medical science that has provided key tools for biomarker discovery in cancer and other human diseases. Proteomics refers to the comprehensive study of all proteins (including their identification, relative abundance, distribution, function, post-translational modifications, and interactions with other macromolecules) in a cell or tissue. It aims to correlate the functional diversity of proteins with the physiological status of the cell or tissue. Systematic proteomic studies are important because proteins perform the main cellular functions that control cell growth, differentiation, proliferation, and death. To identify biomarkers for gastric cancer, we are using multiple proteomic approaches (gel-based and gel-free strategies) to compare the protein profiles of malignant and normal (I) gastric tissues and (II) gastric fluid, to identify differentially expressed proteins.

Mac M.F. HO Principal Investigator DPhil (Oxon) dmshmf@nccs.com.sg

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Research Staff Celine Seow Ching CHUA Huimin CHUA Siok Yuen KAM


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

We reasoned that the transformation from normal gastric epithelium to preneoplastic states and eventually to gastric carcinoma will entail a sequence of molecular and genetic changes that will affect protein expression. Identification of abnormal protein expression in pre-neoplastic and malignant biological samples should lead to the discovery of candidate biomarkers for diagnosis, prognosis, and as therapeutic targets. This study is conducted in collaboration with the Kon laboratory (Applied Human Genetics), clinicians from the Singapore General Hospital (General Surgery, Gastroenterology, and Pathology), Union Hospital (Wuhan, China), and technical specialists from Agilent Technologies and Applied Biosystems.

Figure 2. Representative silver-stained two-dimensional electrophoresis gels of proteins isolated from normal (A) and tumour (B) gastric tissues. Examples of differentially expressed proteins in gastric cancer are highlighted by arrows.

From our gel-based analysis of gastric tissues, we have identified several differentially expressed proteins in gastric cancer (Figure 2). Some of these proteins are well-characterised (e.g. heat shock proteins) while others are novel. For novel proteins, we are conducting further analysis to determine their biochemical properties and their role, if any, in gastric oncogenesis (Figure 3).

Selected Publications Zhu X, Rivera A, Golub MS, Peng J, Sha Q, Wu X, Song X, Kumarathasan P, Ho M, Redman CM, Lee S Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel). Am. J. Hematol. (2009) 84(8):492-8. Kon OL, Yip TT, Ho M, Chan WH, Wong WK, Tan SY, Ng WH, Kam SY, Eng AKh, Ho P, Viner R, Ong HS, Kumarasinghe MP The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile. BMC Med. Genomics (2008) 1:54. Wenzel K, Zabojszcza J, Carl M, Taubert S, Lass A, Harris CL, Ho M, Schulz H, Hummel O, Hubner N, Osterziel KJ, Spuler S Increased susceptibility to complement attack due to down-regulation of decayaccelerating factor/CD55 in dysferlindeficient muscular dystrophy. J. Immunol. (2005) 175(9):6219-25. Ho M, Post CM, Donahue LR, Lidov HG, Bronson RT, Goolsby H, Watkins SC, Cox GA, Brown RH Jr Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency. Hum. Mol. Genet. (2004) 13(18):19992010. Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown Jr RH, Holleran WM, Hanada K Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J. Clin. Invest. (2002) 110(9):1301-8. Ho M, Gallardo E, McKenna-Yasek D, De Luna N, Illa I, Brown RH Jr A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann. Neurol. (2002) 51(1):129-33.

Figure 3. Immunohistochemical analysis of a candidate biomarker in normal, preneoplastic, and neoplastic gastric tissues to evaluate its utility as a marker for early detection of gastric cancer.

Ho M, Amato A, Brown RH Jr Dysferlinopathies in Structural and Molecular Basis of Skeletal Muscle Diseases. (G. Karpati, ed), pp29-32, ISN Neuropath Press, Basel (2002).

II. Investigating the Gastric Oncogenesis Pathway The differentially expressed proteins identified in our biomarker discovery program may provide insights into the gastric oncogenesis pathway. Using these proteins as leads, we are reconstructing the gastric oncogenic pathway by characterising their biochemical properties and identification of their interacting partners. For proteins that are novel, we are developing genetically engineered mouse models to elucidate their function and their role in the pathogenesis of gastric cancer. These animal models should be useful for dissecting the gastric oncogenesis pathway and for testing new therapies and drugs. > 39


WEE KIM WEE LABORATORY OF SURGICAL ONCOLOGY

Our laboratory aims to individualise cancer therapeutics by integrating basic biology with translational research in head and neck cancers, and using the appropriate platforms to: 1. Identify and understand the genes or factors involved in the cell-death pathways 2. Determine DNA damage response pathways involved in cancer stem cell biology 3. Identify genetic determinants and potential biomarkers that can direct cancer therapy in future

In the last few decades, advances in cancer research have highlighted the complexities involved in dealing with cancer. Cancer progression is an evolving multi-pronged process involving the deregulation of pathways that control cell growth and cell death. Furthermore, we now know that tumours comprise a heterogeneous group of cells which contain a subpopulation of highly aggressive cells, which are probably responsible for tumour growth, metastases and resistance to treatment. A small remnant population is sufficient to repopulate and reconstitute the tumour - the cancer stem cell hypothesis. An understanding of the pathways involved in cell death and how these confer selective resistance to conventional methods of killing cancer cells, which utilise chemotherapy and radiotherapy, would be critical to the future of cancer therapeutics. As these abnormalities may exist in various permutations, it is believed that the future of cancer therapy is in individualising treatment to the genetic profile of each tumour, in each patient. In our laboratory, we have taken a three-pronged approach to deal with this issue. The first two involve basic biological techniques aimed at identifying novel, hitherto uncharacterised pathways that modify cellular response to chemo- and radiotherapy, especially those deregulated in cancer stem cells. The third is a translational approach, using molecular profiling to identify markers that predict the behaviour of head and neck cancers under different circumstances.

Factors Involved in the Cell-death Pathways The eventual aim of chemo- and radiotherapy is to induce death specifically in cancer cells. Cell death or apoptosis is a well-orchestrated process regulated by several players, mainly involving the p53 protein. However, it is well known that the p53 pathway is disrupted in a large majority of cancers. Hence, we aim to identify and study novel candidates involved in cell death, independent of p53 function. In this regard, we have identified KLF5 as an important modulator of cell death, which appears to function even in the absence of p53, through a protein called Pim1. Using cellular models we have identified mechanisms through which these proteins function, and use these pathways to promote cell death in a p53-independent manner. We are currently in the process of testing several inhibitors of KLF5 and Pim1 and assessing their role as novel chemotherapeutic agents.

N Gopalakrishna IYER Principal Investigator MBBS (Hons), FRCS(Gen), FAMS, PhD (Cambridge) gopaliyer@nccs.com.sg Hiang Khoon TAN Co-Investigator, Senior Consultant, Department of Surgical Oncology MBBS (Singapore), FRCS (Edin), PhD Tan.H.K@nccs.com.sg > 40

Research Staff Claramae CHIA Fui Teen CHONG Hui Sun LEONG Su-Ghim SIA


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Head and Neck Cancer Stem Cells It is believed that all tumours have small subpopulation of cells, which have an aggressive phenotype, and are able to withstand the damage induced by chemotherapy and radiotherapy. This population is called cancer stem cells, and it is the survival of these cells after conventional therapy that results in recurrent disease and distant metastasis. We have optimised a number of techniques to isolate these cells. Early experiments also show that these are resistant to radiotherapy and chemotherapy, and continue to proliferate despite the effects of these treatment modalities. We are currently in the process of elucidating the mechanisms through which these cells evade death, and whether any of these pathways are amenable to targeting by available or novel compounds.

Selected Publications Tan HK, Saulnier P, Auperin A, Lacroix L, Casiraghi O, Janot F, Fouret P, Temam S Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas. Br. J. Cancer (2008) 99(2):357-63. Zhao Y, Hamza MS, Leong HS, Lim CB, Pan YF, Cheung E, Soo KC, Iyer NG Kruppel-like factor 5 modulates p53independent apoptosis through Pim1 survival kinase in cancer cells. Oncogene (2008) 27(1):1-8. Iyer NG, Xian J, Chin SF, Bannister AJ, Daigo Y, Aparicio S, Kouzarides T, Caldas C p300 is required for orderly G1/S transition in human cancer cells. Oncogene (2007) 26(1):21-29.

Molecular Profiling of Head and Neck Cancers Head and neck cancers (HNCs) pose a significant world-wide public-health threat, branded with one of the lowest survival rates with fewer than 50% of patients surviving more than five years. Current treatment strategies in managing these cancers involve a multimodality approach, with a combination of surgery, chemo- and radiotherapy. Unfortunately, despite advances in detection and treatment of these cancers, survival rates remain alarmingly low. Furthermore, there is a disturbing trend that the incidence of oral / tongue cancers is increasing in younger age groups in several countries. One of the major paradoxes apparent in oral cancers is the inexplicable imbalance between disease burden and the theoretical ease in decreasing mortality with early detection. One attractive explanation for this imbalance is that these cancers are heterogeneous in nature, thus requiring more precise diagnostic and prognostic tools to permit individualised treatment. Our approach to dissecting the heterogeneity of HNCs is based on several key prerequisites that few other institutions can match:

Ahmed AA, Mills AD, Ibrahim AE, Temple J, Blenkiron C, Vias M, Massie CE, Iyer NG, McGeoch A, Crawford R, Nicke B, Downward J, Swanton C, Bell SD, Earl HM, Laskey RA, Caldas C, Brenton JD The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes Ovarian Cancers to Paclitaxel. Cancer Cell (2007) 12(6):514-527. Bundyc JG*, Iyer NG*, Gentile M, Hu DE, Kettunen M, Maia AT, Caldas C, Brindle KM Metabolic consequences of p300 gene deletion in human colon cancer cells. Cancer Res. (2006) 66(15):7606-7614. Iyer NG, Chin SF, Ozdag H, Daigo Y, Hu DE, Cariati M, Brindle K, Aparicio S, Caldas C p300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels. Proc. Natl. Acad. Sci. (2004) 101(19):7386-7391. *Co-first author.

1) Tissue repositories, collecting a spectrum of clinical material 2) Clinical databases 3) Easy access to technology, which in our case involves established Affymetrix based microarray profiling techniques and next generation sequencing technology (Solexa) Using these platforms, we intend to identify genetic determinants and potential biomarkers that can direct future therapy. These have been divided in several well-established clinical scenarios: 1) Recurrence of early oral cancers despite optimum treatment 2) Comparing classical oral cancers versus oral cancers in young patients 3) Metastatic markers in nasopharyngeal cancers Data obtained from these studies would be crucial in future prospective studies to establish these signatures as therapeutic guides or in the discovery of novel pathways involved in HNC carcinogenesis.

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LABORATORY OF APPLIED HUMAN GENETICS

The Laboratory of Applied Human Genetics focuses on (a) gastric cancer research; and (b) developing cellular therapy for metabolic disorders. The model metabolic disorders we work on are diabetes mellitus and haemophilia A because current treatments are sub-optimal, costly or both. Gastric cancer causes more cancer deaths worldwide (> 700,000 each year) than all other cancers, except lung cancer, despite good evidence that gastric cancer should be both preventable and curable. Our work aims to translate the curable potential of gastric cancer into real cures for nearly one million new patients diagnosed each year with this lethal cancer. Our research focuses on identifying molecular alterations (chromosomes, genome, genes and proteins) that are reliable signatures of gastric cancer. This should enable development of sensitive and accurate detection methods for highly curable early stage gastric cancer and could provide clues for new treatments for patients whose cancers cannot be totally eradicated by surgery.

Gastric Cancer As a result of its declining incidence, gastric cancer now accounts for only 10% of all new cancer cases globally. However, this favourable trend has not been matched by increasing cure rates. Gastric cancer thus retains its pole position as the second most common cause of cancer mortality worldwide. Two-thirds of gastric cancer cases are in the developing countries and there is a particularly high incidence among East Asians. Gastric cancer is both preventable and curable. Paradoxically, it continues to be one of the more lethal cancers, having an overall 5-year survival rate of about 23% that is considerably lower than other common cancers e.g. breast and colorectal cancer, partly because curative treatments for gastric cancer have been relatively intractable to significant improvements. Our efforts are directed at addressing the disparity between the potential and actual curability of gastric cancer. We aim to (a) develop detailed and comprehensive pathway maps of molecular and cellular changes that lead to gastric cancer; (b) identify biomarkers for sensitive and accurate detection of curable early stage gastric cancer; (c) identify and molecularly characterise signature translocations in gastric cancer; and (d) document the activated kinome in gastric cancer as a means of developing targeted therapies to complement surgical resection – currently the only curative treatment; (e) search for and characterise candidate tumour-initiating cells. Our lines of serially passageable xenotumours in immunocompromised mice established from surgically resected gastric adenocarcinomas are a resource in our search for tumour-initiating cells and for testing kinase modulators. We have discovered a multiprotein profile in endoscopic gastric fluid samples that diagnoses gastric cancer with 93% specificity and 88% sensitivity (Figure 1). Building on this pilot study, our collaborators are now expanding and refining the biomarker study to a larger number of subjects in Singapore and China using protein mass spectrometry.

Oi Lian KON Principal Investigator & Head, Division of Medical Sciences MBBS, FRCPC Diplomate ABIM, MD dmskol@nccs.com.sg

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Research Staff Nelson K.F. CHEN Tiannan GUO Sivalingam JAICHANDRAN Frank Myo Lwin KYAW Louise S.S. LEE Siew Hong LEONG Wai Har NG


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Our lab has identified several chromosomal translocations of high frequency in gastric cancer cell lines. We have found disruptions of chromosome 18q in about 50% of gastric cancer tissues, among which 20% show fusion of chromosome 18q with chromosomes 6, 8 or 9 (Figure 2). Of interest, we have observed a high frequency of chromosome 18q disruptions also in lung cancer tissues but not in non-gastric cancers. The lab is now focused on molecularly characterising this and other signature chromosome breakpoints and fusions using a range of techniques such as chromosome sorting, deep sequencing, bioinformatics and fluorescence in situ hybridization on tissue microarrays. We also collaborate in projects directed at documenting the gastric proteome and phosphoproteome in particular, as another entree into the molecular pathways of gastric oncogenesis.

Figure 1: Gastric fluid: cancer biomarker profile.

Figure 2: Gastric cancer chromosomal translocation.

Cellular Therapy of Metabolic Disorders Work from our lab has shown that autologous primary hepatocytes can be modified to serve as an effective source of insulin secretion in a large preclinical model of diabetes. Liver cells were prepared from diabetic YorkshireLandrace pigs. After introducing an insulin gene, the modified liver cells were immediately re-implanted into the liver of the same pig. This study resulted in significant metabolic improvement of severe diabetes. It also showed that diabetes inflicts damage on multiple target tissues within weeks of onset and that early metabolic correction has significant benefit in this regard (Figure 3). We have now shown that primary bone marrow stromal cells can be modified to acquire glucose-responsive insulin secretion. Pending funds, this approach will be tested in an autologous setting in diabetic YorkshireLandrace pigs as proof-of-concept, prior to possible clinical trials. Figure 3: Basement membrane

In other work related to cell therapy, we have thickening of choroidal capillaries in diabetic pigs is corrected by evaluated the biosafety of site-directed treatment with autologous insulintransgene integration using the phiC31 secreting hepatocytes. integrase system. We are currently assessing the feasibility of employing zinc finger nucleases for site-specific transgenesis in umbilical cord-lining cells with the goal of developing autologous bioimplants that could restore coagulation factor VIII production in hemophilic patients (Figure 4). Figure 4: Secretion of human coagulation factor VIII by primary human umbilical cord lining cells stably integrated with the transgene.

Selected Publications Guo T, Lee SS, Ng WH, Zhu Y, Gan CS, Zhu J, Wang H, Huang S, Sze SK, Kon OL Global molecular dysfunctions in gastric cancer revealed by an integrated analysis of the phosphoproteome and transcriptome. Cellular and Molecular Life Sciences (2010) In Press. Guo T, Zhu Y, Gan CS, Lee SS, Zhu J, Wang H, Li X, Christensen J, Huang S, Kon OL, Sze SK Quantitative proteomics discloses MET expression in mitochondria as a direct target of MET kinase inhibitor in cancer cells. Molecular & Cellular Proteomics (2010) In Press. Chen NKF, Tan SY, Udolph G, Kon OL Insulin expressed from endogenously active glucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetes therapy. Gene Therapy (2010) 17(5):592-605. Jaichandran S, Shruti K, Ng WH, Lee SS, Phan TT, Kon OL Biosafety assessment of site-directed transgene integration in human umbilical cord-lining cells. Molecular Therapy (2010) 18(7):13461356. Li G, Luo R, Zhang J, Yeo KS, Lian Q, Xie F, Tan EKW, Caille D, Kon OL, SaltoTellez M, Meda P, Lim SK Generating mESC-derived insulinproducing cell lines through an intermediate lineage-restricted progenitor line. Stem Cell Research (2008) 2(1):41-55. Kon OL, Yip TT, Ho M, Chan WH, Wong WK, Tan SY, Ng WH, Kam SY, Eng AKH, Ho P, Viner R, Ong HS, Kumarasinghe MP The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile. BMC Medical Genomics (2008) 1:54. Guo T, Gan CS, Zhang H, Zhu Y, Kon OL, Sze SK Hybridization of pulsed-Q dissociation and collision-activated dissociation in linear ion trap mass spectrometer for iTRAQ quantitation. J. Proteome Res. (2008) 7(11):4831-4840. Chen KF, Wong JS, Kee IH, Lai SH, Thng CH, Ng WH, Ng RT, Tan SY, Lee SY, Tan ME, Sivalingam J, Chow PK, Kon OL Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model. PLoS ONE (2008) 3(3):e1734. Hou Q, Wu YH, Grabsch H, Leong SH, Tang BL, Kon OL, Tan P Integrative genomic analysis identifies RAB23 as an invasion mediator gene associated with diffuse type gastic carcinoma. Cancer Res. (2008) 68(12): 4623-4630. > 43


LABORATORY OF MOLECULAR ONCOLOGY

Breast cancer is the most common cancer among women in Singapore, with a rising incidence. Our research focuses on the study of breast cancer susceptibility genes in our local Asian population, using a comprehensive molecular and bioinformatic strategy. In addition, our group is utilising genetic and genomic approaches to identify novel cancer related genes for potential application in cancer prevention and treatment.

Breast Cancer Susceptibility Breast cancer is the most common cancer among women in Singapore, with an age-standardised rate of 57.1 per 100,000 per year, which translates to approximately 1,300 new cases being diagnosed each year. The majority of breast and ovarian cancers are “sporadic� cancers, however, between 5% and 10% of all breast cancer cases are hereditary. Mutations in two breast cancer susceptibility genes, called BRCA1 and BRCA2, occur in patients with hereditary breast and ovarian cancer. Women who carry a mutated BRCA1 or BRCA2 gene have a significantly higher risk of developing breast cancer by age 70, of between 40 to 80%. Recent studies have also implied treatment differences for cancers developing in such patients. Other genes such as TP53 and PTEN, with an autosomal dominant pattern of inheritance, may also play a role in patients with hereditary breast cancer, and their contribution can be identified through risk assessment and genetic testing. The research goal of our laboratory is to expand on strategies that can improve the detection rate of mutations in breast cancer susceptibility genes in our local Asian population. We are focussing on discovering genes associated with susceptibility and developing efficient methods for mutation detection, with the long-term aim of cancer prevention and early cancer detection.

Figure 1: Schematic diagram showing the 8.46kb Alu-mediated BRCA1 exon 13 duplication. AluSp in intron 12 (grey); AluSq in intron 13 (black). (For more details, please refer to Clin. Genet. (2006) 70:80-82)

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Ann S.G. LEE Principal Investigator BSc (Hons), MSc, DPhil (Oxon) dmslsg@nccs.com.sg

Eric YAP Adjunct Principal Investigator MBBS (Hons), DPhil (Oxon) ericyap@ymail.com

Peter ANG Visiting Consultant & Associate Investigator MBBS, MMed (Int Med), MRCP (UK) , FAMS (Med Oncol) peter_ang@source-link.net

Research Staff Maurice CHAN, (PhD) Jia Mei CHUA, BSc(Hons) Joshua WONG, BSc(Hons) Shenmo JI, (DipBiotech)


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Selected Publications

(a) Exon 13 duplication with elevated peak.

(b) Result for a normal control. Figure 2: Detection of an exon 13 rearrangement in the BRCA1 gene using multiplex ligation-dependent probe amplification (MLPA). Arrows indicate the peak for exon 13 in (a) and (b).

Research Highlights of our Laboratory •

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Our team reported the identification of a BRCA1 founder mutation among breast cancer patients of Malay ethnicity (Human Mutation (2003) 22:178. Mutation in Brief #633, 1-8). We have developed a comprehensive screening strategy for improved BRCA1 and BRCA2 mutation screening for breast and/or ovarian cancer patients. The strategy incorporates the detection of large genomic rearrangements, evaluation of splice site alterations and the computational evaluation of missense mutations (Clin Genet (2006) 70:80-82; Cancer Epidemiol Biomarkers Prev (2007) 16:2276-84; Amino Acids (2008) 35:615-26). We have recommended that screening for the CHEK2*1100delC mutation in Asian women with a family history of breast cancer is unwarranted, in contrast to recommendations for such screening in Northern or Eastern European women with a similar history (J Clin Oncol (2008) 26:2419). We have identified the first family in Singapore with Li-Fraumeni syndrome (Clin Genet (2009) 75:294-7). We have identified a gene that has tumour suppressive functional characteristics in breast and colorectal cancer (Oncogene (2009) 28:4189200).

Ong DCT, Ho YM, Rudduck C, Chin K, Kuo W-L, Lie DKH, Chua CLM, Tan PH, Eu KW, Seow-Choen F, Wong CY, Hong GS, Gray JW, Lee AS* LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer. Oncogene (2009) 28(47):4189-200. Ang P, Lim IHK, Yong RYY, Lee AS* A molecular approach for identifying individuals with Li-Fraumeni Syndrome who have a limited family history. Clin. Genet. (2009) 75(3):294-7. Lee AS*, Ang P CHEK2*1100delC screening of Asian women with a family history of breast cancer is unwarranted. J. Clin. Oncol. (2008) 26(14):2419. Ang P, Lim IH, Lee TC, Luo JT, Ong DC, Tan PH, Lee AS* BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive detection strategy. Cancer Epidemiol. Biomarkers and Prev. (2007) 16(11):2276-84. Lai PS, Cheah PY, Kadam P, Chua CL, Lie DK, Li HH, Eu KW, Seow-Choen F, Lee AS* Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas. Int. J. Cancer (2006) 119(5):1061-1066. Toh HC, Teo M, Ong KW, Lee V, Chan E, Lee AS, Vathsala A Use of sirolimus for Epstein-Barr viruspositive smooth-muscle tumour. Lancet Oncol. (2006) 7(11):955-957. *Corresponding author.

Current Research Interests Cutting edge technologies for mutation screening and genotyping, such as high resolution melting analysis, next generation sequencing and bioinformatic analysis are currently being employed for the discovery and validation of new biomarkers for cancer and to understand the molecular mechanisms of drug resistance in Mycobacterium tuberculosis. In collaboration with oncologists at our Centre, we are also actively engaged in translational cancer research projects aimed at identifying novel biomarkers for patient stratification for improving treatment strategies of breast cancer patients.

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LABORATORY OF LIVER CANCER FUNCTIONAL GENOMICS

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and especially so in the Asia Pacific region. Our laboratory’s key research goal is to elucidate the molecular pathway(s) leading to HCC. Using a cDNA microarray approach, we have identified several genes that are significantly differentially expressed between the tumour and adjacent normal tissues and are in the process of characterising some of them.

I. Functional Genomics of Hepatocellular Carcinoma Interestingly, we found that cells over-expressing one of these genes escape mitotic arrest and have more variable chromosome numbers per cell. We hope that this gene or other novel genes identified through cDNA microarray approach will serve as: (a) prognostic markers, or (b) markers to identify individuals who are at high risk of developing HCC, or identify (c) markers to identify individuals at high risk of having recurrence of the tumour in HCC patients. We also hope that target-specific therapies can be developed with the identification of the pathway(s) responsible for HBV-associated HCC. Infection by the Hepatitis B virus HBV is predominant in HCC patients in this part of the world. Hence, we are utilising ultra-high throughput technologies to fully characterise the HBV DNA, integrants and transcript in Singaporean HBV-associated HCC patients so as to identify HBV chimeras/variants that may be associated with poor prognosis and help us elucidate their role in tumorigenesis. Another research focus of our lab is to examine the role that HBx, a protein in HBV, plays in the carcinogenesis process. As HBx is a known transcriptional coactivator, we are utilising high throughput strategies to identify and characterise deregulated direct gene targets of HBx from indirect protein-DNA binding as well as transcriptional factors directly interacting with HBx. We are also examining if HBx can deregulate miRNAs which is often deregulated in HCC patients.

Caroline G.L. LEE Principal Investigator PhD dmslgl@nccs.com.sg Joint Appointments: Associate Professor, Department of Biochemistry, National University of Singapore Associate Professor, Duke-NUS Graduate Medical School

Research Staff Cheryl CHAN Way Champ MAH Lizhen LIU Jianwei REN Pui Hoon SEW Steven Setiawan THENG Su Ting TOH JingBo WANG Yu WANG Yin Yee WONG Jin YU Clinical Attachment Grace PANG (MBBS)

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

II. Human / Pharmaco Genetics

Selected Publications

Polymorphisms are known to contribute to variations in disease susceptibility or drug response. Although millions of polymorphisms have been found in the human genome, not all of these polymorphisms affect phenotype or are causally associated with disease risk or drug response. Our laboratory focuses on identifying potentially functionally significant polymorphisms that may be useful for disease/drug response association studies. We utilised more than 40 different resources to select a set of potentially functional SNPs (pfSNPs) database based on their predicted/inferred functional significance as well as documented disease-association/functional importance. We are validating our resource for its usefulness in disease/drug response association studies.

SUNG W-K, LU Y, LEE WH Charlie, ZHANG D, RONAGHI M, LEE GL Caroline Deregulated Direct Targets of the Hepatitis B Viral (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling. J. Biol. Chem. (2009) 284(33):21941 – 21954.

Our laboratory is also interested in understanding the architecture and population distribution of polymorphisms in the human genome. We are focusing on SNPs that are significantly different amongst different ethnic groups to evaluate if some of these SNPs may account for the great variation in drug response / disease susceptibility amongst different ethnic groups.

Wang Y, Lee AT, Ma JZ, Wang JB, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG Profiling microRNA Expression in Hepatocellular Carcinoma reveals microRNA-224 Upregulation and Apoptosis Inhibitor-5 as a microRNA-224Specific Target. J. Biol. Chem. (2008) 283(19):1320513215. Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG Signatures of Recent Positive Selection at the ATP-Binding Cassette (ABC) Drug Transporter Superfamily Gene Loci. Hum. Mol. Genet. (2007) 16(11):13671380. Ren J, Kan A, Leong SH, Ooi LL, Jeang KT, Chong SS, Kon OL, Lee CG Fat10 plays a role in the regulation of chromosomal stability. J. Biol. Chem. (2006) 281(16):1141311421. Wang Z, Wang B, Tang K, Lee EJ, Chong SS, Lee CG A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection. Hum. Mol. Genet. (2005) 14(14):20752087. Lee AT, Ren J, Wong ET, Ban KH, Lee LA, Lee CG The hepatitis B virus X protein sensitizes HepG2 cells to UV light- induced DNA damage. J. Biol. Chem. (2005) 280(39): 3352533535.

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TAN CHIN TUAN LABORATORY OF OPTICAL IMAGING AND PHOTODYNAMIC THERAPY OF CANCER

We are the pioneers in clinical applications of fluorescence diagnosis and photodynamic therapy (PDT) in Singapore. The focus of this laboratory is to investigate minimally invasive methods in cancer detection and therapy using biophotonics applications and nano-biotechnology for oral and bladder cancers. The novel optical methods being investigated are fluorescence endomicroscopy, surface enhanced Raman spectroscopy (SERS), optical imaging of nanogold conjugated biomarkers as contrast agents in optical coherence tomography (OCT) and reflectance spectroscopy. PDT is a promising alternative cancer treatment modality that is known to be able to activate the body’s anti-tumour immunity. The laboratory is investigating the treatment of head and neck and bladder cancers using new generation photosensitisers.

Early Cancer Detection Using Optical Imaging Techniques We have a multidisciplinary, highly interactive research environment comprising clinicians, physicists, biologists, chemists, pharmacists and computer engineers. We are currently employing optical imaging techniques to investigate bladder and oral cancers. Our major objective is to devise real-time optical imaging systems. We are also implementing fluorescence and autofluorescence image processing software and endomicroscopic approaches to develop an optical biopsy technique to stage cancer (Figure 1). This may prove to be a superior method to the current widely used white light endoscopy. We are exploring the use of nanotechnology in combination with biophotonics for molecular imaging for early cancer detection. Nanoparticles combined with biomakers would be used as contrast agents in novel optical coherence tomography and reflectance based imaging. We also focus on SERS-based nanophotonics of biofluids of proteins and aptamers for early cancer detection. Our ex-vivo methods in fluorescence based cytology of urine and saliva combines the use of multiphoton confocal microscopy and fluorescence lifetime imaging to grade cancer histopathologically. We are currently developing sensitive biocompatible SERS nanotags for in-vivo sensing and imaging of head and neck cancers. We have also successfully developed quantum dot capped magnetite nanorings as high performance nanoprobe for multiphoton fluorescence and magnetic resonance imaging (Figure 2). Terahertz Time-domain spectroscopy (THz -TDS) technology is being tested for early-stage cancer diagnosis. A catheter-based OCT probe for a 3D volumetric diagnosis of cancer by incorporating microelectromechanical systems (MEMS) technology to OCT.

Khee Chee SOO Principal Investigator & Director, National Cancer Centre Singapore MBBS, MD, FRACS, FACS, FAMS admskc@nccs.com.sg

Malini Carolene OLIVO Co-Principal Investigator BSc, BEd (Hon), PhD dmsmcd@nccs.com.sg

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Research Staff Nagamani DENDUKURI (PhD) Kiang Wei KHO (PhD) Patricia S.P. THONG (PhD) Bhuvaneswari RAMASWAMY Lucky SASIDHARAN Chuan Sia TEE


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Selected Publications

F i g u re 1 . R e a l - t i m e m e a s u re m e n t o f microstructures and reconstruction of optical slices stack to achieve 3D visualization using confocal endomicroscopy of mouse tongue.

Figure 2. Representative two-photon fluorescence image (756 nm excitation) of the stained bladder cancer cells with (a) yellow- and (b) red-colored internalized quantum dots (QDs) capped magnetite nanorings.

Photodynamic Therapy Using New Generation Photosensitisers and their Formulations In the area of cancer therapy we are investigating the novel use of photosensitiser and light to treat cancer as an alternative modality in inoperable cancers. Our aim is to develop novel nano-photosensitisers for clinical application in head and neck and bladder cancers. By studying the photobiology of these novel compounds in terms of its mechanism of action in both cellular (apoptosis and necrosis) and vascular modes, we strive to better understand the tumour response to PDT. Combination treatment modalities with immunotherapy and anti-angiogenesis therapy to enhance the efficacy of PDT are also being investigated. In the area of photobiology, we aim to develop virosomes (a reconstituted virus envelope) as targeted delivery vehicles of a chlorin based photosensitiser (Ce6) using a monoclonal antibody as a molecular specific contrast agent targeted against EGFR for in vivo assessment of oral cancer (Figure 3). During our pilot clinical trial using PDT for treatment of recurrent angiosarcoma, we have observed PDT-induced anti-tumour immunity against both treated and untreated distant tumours (Figure 4). We hypothesized that PDT can activate a cell-mediated immune response against untreated tumours. This was supported by immunohistochemistry of biopsies from a lesion showing a shift from CD4+ to CD8+ dominance in the T lymphocyte infiltrate. In conclusion, PDT is a promising alternative modality for cancer therapy and is suitable for use in lesions that are accessible to an endoscope. PDT also offers good cosmetic results with excellent normal tissue regeneration and minimal systemic toxicity. Figure 3. Virosome as a targeted delivery vehicle of a photosensitiser using a monoclonal antibody and gold nanoparticle as a molecular-specific contrast agent targeted against EGFR for in vivo assessment of epithelial neoplasia.

Bhuvaneswari R, Thong PS, Gan YY, Soo KC, Olivo M Evaluation of hypericin-mediated photodynamic therapy in combination with angiogenesis inhibitor bevacizumab using in vivo fluorescence confocal endomicroscopy. J. Biomed Opt. (2010) 15(1): 011114. Chin WW, Praveen T, Heng PW, Olivo M Effect of polyvinylpyrrolidone on the interaction of chlorin e6 with plasma proteins and its subcellular localization. Eur. J. Pharm. Biopharm. (2010) 76(2):245-252. Thong PS, Olivo M, Chin WW, Bhuvaneswari R, Mancer K, Soo KC Clinical application of fluorescence endoscopic imaging using hypericin for the diagnosis of human oral cavity lesions. Br. J. Cancer (2009) 101(9):1580-1584. Bhuvaneswari R, Gan YY, Soo KC, Olivo M Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumour response. Mol. Cancer (2009) 8:94. Chin WW, Thong PS, Bhuvaneswari R, Soo KC, Heng PW, Olivo M In-vivo optical detection of cancer using chlorin e6--polyvinylpyrrolidone induced fluorescence imaging and spectroscopy. BMC Med. Imaging (2009) 9:1. Kho KW, Qing ZM, Shen ZX, Ahmad IB, Lim SS, Mhaisalkar S, White TJ, Watt F, Soo KC, Olivo M Polymer-based microfluidics with surfaceenhanced Raman-spectroscopyactive periodic metal nanostructures for biofluid analysis. J. Biomed. Opt. (2008) 13(5):054026. Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo, M, Soo KC Photodynamic Therapy-Activated Immune Response Against Distant Untreated Lesions In Recurrent Angiosarcoma. Lancet Oncol. (2007) 8(10):950-952. Kho KW, Shen ZX, Lei Z, Watt F, Soo KC, Olivo M Investigation into a surface plasmon related heating effect in surface enhanced Raman spectroscopy. Anal. Chem. (2007) 79(23):8870-8882. Kah JC, Kho KW, Lee CG, Sheppard R, Shen ZX, Soo KC, Olivo M Early Diagnosis of Oral Cancer based on the Surface Plasmon Resonance of Gold Nanoparticle. Int. J. Nanomed. (2007) 2(4):785-798.

Figure 4. Angiosarcoma on upper limbs (a) main cluster before PDT on right upper limb, (b) scarring at site treated with PDT and spontaneous regression of untreated tumours on right upper limb 18 months after treatment, (c) tumours on left upper limb before PDT, (d) spontaneous regression of untreated tumours on left upper limb 4 months after PDT.

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LABORATORY OF CELL THERAPY AND CANCER VACCINE

Our laboratory’s main focus is on bench-to-bedside translational research into immune-based cancer therapies. The immune system identifies and destroys foreign antigens by discriminating ‘self’ from ‘non-self’ antigens. Although cancer cells originate from patients’ own cells, they may be recognised as foreign and attacked by the immune system due to expression of tumour-associated antigens that are not normally expressed by normal cells. We believe that immunotherapy has the potential to develop into a relevant therapeutic option and may offer potential benefits to cancer patients. Thus, we have developed clinical cell-based immunotherapeutic strategies including nonmyeloablative blood stem cell transplantation, dendritic cell cancer vaccines and T cell therapies for solid tumours.

Our first cell therapy clinical trial was a non-myeloablative blood stem cell transplantation +/- delayed donor lymphocyte infusion therapy for twenty-one refractory Stage IV nasopharyngeal carcinoma (NPC) patients. NPC is an Epstein-Barr virus (EBV)-associated cancer endemic in southern China and South-East Asia. 37% of patients evaluated achieved significant tumour shrinkage (partial response, PR) and 16% achieved stable disease (SD), for an overall disease control rate of 53%, with evidence for delayed graft-versus-tumour responses. In collaboration with Dandrit Biotech A/S, we completed a Phase II clinical trial of an allogeneic lysate-pulsed autologous dendritic cell (DC) cancer vaccine (MelCancerVac®) in twenty advanced colorectal cancer patients. The study was initiated in January 2006 and completed in October 2008. Our results showed a clinical benefit rate of 40% (1 PR and 7 SD), with some patients achieving prolonged disease control. In partnership with the Center for Cell and Gene Therapy (CAGT), Baylor College of Medicine, Houston, Texas, USA, we conducted a DC vaccine clinical trial to treat advanced refractory NPC patients. We vaccinated NPC patients with DCs transduced with a replication-deficient Ad5f35 adenoviral vector encoding LMP-1 and LMP-2, two EBV genes expressed by NPC. Sixteen patients received a combination treatment of this DC vaccine plus celecoxib, a non-steroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, antipyretic and anti-angiogenesis activities. Two patients (12.5%) achieved disease stabilisation for more than 18 weeks and one patient achieved PR, leading to an overall clinical benefit rate of 19%, and the treatment was very well tolerated overall. We have recently initiated another cell-based translational program for treating NPC patients, using adoptive EBVspecific T cell therapy. Autologous EBV-specific cytotoxic T cells in these patients are reactivated and expanded ex vivo from peripheral blood mononuclear cells. This is achieved through repeated stimulation with EBV-transformed autologous lymphoblastoid cell lines (LCL). Previous adoptive CTL studies in a small number of NPC patients had yielded clinical benefits and had been well tolerated. This clinical trial is currently ongoing.

Han Chong TOH Principal Investigator BSc, MBBChir, MRCP, FRCP, FAMS dmothc@nccs.com.sg

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Research Staff Marissa TEO (PhD) Peter Who-Whong WANG (PhD) Chit Lai CHEE Lip Seng KOH Joanna Hui Ting NG Yatanar SOE Elizabeth Yoke Yoke YEO


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Our laboratory is also collaborating with the Department of Renal Medicine at the Singapore General Hospital, to study the molecular characteristics of a rare EBV-related cancer, EBV+ smooth muscle tumour. We are also involved in hepatocellular carcinoma (HCC) translational research. We have carried out various studies to investigate prognostic markers of HCC, both in the intrinsic tumour (seed) and the surrounding microenvironment (soil). We have established a prognostic role for FOXP3+ regulatory T cells in patients with resected HCC as a determinant of overall survival. Other studies involving analysing various immunologic parameters and molecular biomarkers in HCC are ongoing. We are currently further investigating a gene, FOXO3a, a Forkhead box O transcription factor, which we have also established as a prognostic survival marker in this cancer and is part of the AKT/FOXO3a/Pml signaling pathway. We have also established the gene IL12RB1 as a potential prognostic marker in resected HCC and analysed Treg and Th17-related markers in a series of HCC patients. One of our ongoing HCC projects is to study the immune-based signatures in the HCC microenvironment.

Selected Publications Toh HC, Chia WK, Sun L, Thng CH, Soe Y, Phoon YP, Yap SP, Lim WT, Tai WM, Hee SW, Tan SH, Leong SS, Tan EH Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation. Bone Marrow Transplant (2010) Epub ahead of print. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK, Lee KH, Abastado JP, Toh HC, Nardin A Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J. Hepatol. (2010) 52(3):370-9. Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, Phoon YP, Soe Y, Tan SH, Hee SW, Foo KF, Ong S, Koo WH, Zocca MB, Claesson MH Clinical benefit of allogeneic melanoma cell lysate-pulsed autologous dendritic cell vaccine in MAGE-positive colorectal cancer patients. Clin. Cancer Res. (2009) 15(24):7726-36. Kvistborg P, Bechmann CM, Pedersen AW, Toh HC, Claesson MH, Zocca MB Comparison of monocyte-derived dendritic cells from colorectal cancer patients, nonsmall-cell-lung-cancer patients and healthy donors. Vaccine (2009) 28(2):542-7. Ong KW, Teo M, Lee V, Ong D, Lee A, Tan CS, Vathsala A, Toh HC. Expression of EBV latent antigens, mammalian target of rapamycin, and tumor suppression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications. Clin. Cancer Res. (2009) 15(17):5350-8.

Figure 1: Dendritic cells generated in culture. Cells shown in this figure are ready for harvest and used as cancer vaccine.

Toh HC, Sun L, Soe Y, Wu Y, Phoon YP, Chia WK, Wu J, Wong KY, Tan P. G-CSF induces a potentially tolerant gene and immunophenotype profile in T cells in vivo. Clin. Immunol. (2009) 132(1):83-92. Toh HC, Teo M, Ong KW, Lee V, Chan E, Lee AS, Vathsala A Use of sirolimus for Epstein-Barr viruspositive smooth-muscle tumour. Lancet Oncol. (2006) 7(11):955-7. You Z, Huang X, Hester J, Toh HC, Chen SY Targeting dendritic cells to enhance DNA vaccine potency. Cancer Res. (2001) 61(9):3704-11.

Figure 2: Colonies of proliferating EBV-specific T cells in culture.

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BRAIN TUMOUR RESEARCH LABORATORY

In translational research, we seek to develop insights into brain tumour biology and novel treatment strategies. Our laboratory has developed in vitro and in vivo rodent pathologic and MRI brain tumour models, local patient brain tumour cell lines from specimens resected by our neurosurgery colleagues and gene therapy incorporating anti-angiogenic, pro-apoptotic, antisense and stem cell approaches. Our strategy is “from the operating theatre, clinic to research bench� cohesion, marrying basic science with clinical brain tumour problems. Our two areas of research focus are: 1. 2.

Molecular pharmacological studies of glioma chemotherapy Cancer stem cells in the brain

Molecular Pharmacological Studies of Glioma Chemotherapy Gliomas are among the most chemo-resistant types of human cancers. Chemotherapeutic drugs, such as alkylating agents, kill tumour cells through interrupting DNA replication. Tumour cell DNA repair and cell survival capacities are major factors determining chemosensitivity. Our team works on two important pathways of DNA damage induced cell signaling: I. Chemotherapy-induced tumour cell response. Temozolomide (TMZ) is a key-methylating agent for treatment of gliomas and DNA repair (including mismatch repair, DNA double strand break repair etc.) that plays a vital role in mediating TMZ cytotoxicity. Gliomas often have a deregulated cell growth and survival signalling, which significantly confer chemoresistance to TMZ. By using quiescent and proliferating glioma cell models, we are investigating the interaction of DNA repair and cell growth / survival signalling in glioma chemoresistance. We strive to improve tumour cell killing by harnessing novel mechanisms of DNA damage-induced type II program cell death (autophagy). II. Epithelial cell transforming sequence 2 (ECT2) and cell growth control. ECT2 is an oncoprotein, which transforms fibroblast cells following N-terminal truncation. ECT2 is overexpressed in gliomas, and it has been proposed as a potential prognostic marker for glioma tumours. We have found that ECT2 has novel functions in G1-phase cell growth and cell cycle progression. Currently, we are defining the role of ECT2 in G1/S cell cycle transition and oncogenic cell growth, which contain critical cellular signaling events underpinning glioma malignancy and chemosensitivity. Our study of ECT2 will contribute to the understanding of glioma pathology and the improvement of glioma chemosensitivity.

Meng Cheong WONG Principal Investigator MBBS, MMed, MRCP, Dip. Amer. Bd. Neur., FRCP, FAMS, FAAN dmswmc@nccs.com.sg

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Research Staff Khong Bee KANG (PhD) Congju ZHU (PhD) Ian Bolun ZHAO (MSc) Eugene Y M TAN (BSc, Hon) Kareen Y L WONG


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Cancer Stem Cells in the Brain

Selected Publications

Accumulating evidence has implicated cancer as a disease of stem cells. In this context, a small fraction of cancer cells adopt the properties of stem cells such as unlimited self-renewal, contributing to tumourigenesis.

Wong MC, Zhu CJ, Cheng SY Modulators of cell cycle progression. US Provisional Patent (No. 61/263,620) (2009)

Our lab has established several techniques necessary for isolation of clonal Brain Tumour Stem Cells (BTSCs). We have successfully isolated and characterised cancer stem cells from our patients’ primary glioma brain tumours and shown their enhanced DNA repair capacity, as well as enhanced resistance to radiation and chemotherapy.

Kang KB, Zhu C, Yong SK, Gao Q, Wong MC Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy. Mol. Cancer (2009) 8:66-81.

Our study of these important BTSCs will seek to identify novel targets for improved cancer treatment so as to overcome chemo-radioresistance, the primary current cause of brain tumour relapse and recurrence.

Conclusion The Brain Tumour Research Laboratory works closely with clinicians, including neuro-oncologists, neurosurgeons, radiation oncologists and other colleagues to improve molecular and cellular characterisation of brain tumours in our local population, and to improve chemotherapy and biological based therapies (e.g. receptor tyrosine kinase inhibition, immunotherapeutic) in our clinic. We believe that scientific advancement is an integral part of improving survival and quality of life for our brain tumour patients.

Figure 1: MRI brain scans – malignant glioma. Left: Pre-chemotherapy Right: Post-chemotherapy

Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu CJ, Wong MC Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumour angiogenesis with extensive tumour necrosis. Int. J. Radiat. Oncol. Biol. Phys. (2007) 67(3): 888-896. Ty AU, See SJ, Rao JP, Khoo JB, Wong MC Oligodendroglial tumour chemotherapy using “decreased-dose-intensity” PCV: a Singapore experience. Neurology (2006) 66(2):247-249. Moore XL, Lu J, Sun L, Zhu CJ, Tan P, Wong MC Endothelial progenitor cells “homing” specificity to brain tumours. Gene Ther. (2004) 11(10):811-818. Zhu CJ, Li YB, Wong MC Expression of antisense bcl-2 cDNA abolishes tumorigenicity and enhances chemosensitivity of human malignant glioma cells. J. Neurosci. Res. (2003) 74(1):60-66. Zhu CJ, Cheng SY, Teng SW, Moore XL, Wong MC Temozolomide induces a network signaling of DNA repair in human malignant glioma cells. Eur. J. Biochem. (2003) 270(suppl):140. Wu M, Das A, Tan Y, Zhu CJ, Cui T, Wong MC Induction of apoptosis in glioma cell lines by TRAIL/Apo-2l. J. Neurosci. Res. (2000) 61(4): 464-470.

Figure 2: Growth of primary culture from brain tumour tissues as neurospheres (left) and differentiated glioma cells (right).

Figure 3: Immunofuorescence staining of neurospheres and differentiated progenies.

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NATIONAL CANCER CENTRE SINGAPORE – VAN ANDEL RESEARCH INSTITUTE TRANSLATIONAL RESEARCH LABORATORY The NCCS-VARI translational research laboratory has several functions. Scientifically, it focuses on genomic profiling of Asian cancers using cutting-edge technologies such as third-generation sequencing – the data is then correlated with clinicopathological information including how patients respond to certain drugs. The goals are to 1) understand the molecular mechanism underlying these cancers; 2) to identify novel biomarkers than can help determine the nature and behavior of the disease as well as predicting patients’ response to certain drugs; and 3) to identify novel therapeutic targets that can be further developed into cancer drugs. In collaboration with practicing oncologists, the group is conducting research to understand the mechanisms of certain drug resistance that have been used in treating certain cancer types. The group has hosted and trained clinician scientists, both locally and abroad, who are interested in pursuing translational research. To date, the laboratory has been instrumental in establishing several cancer type-based translational research groups at the National Cancer Center Singapore including lymphoma, sarcoma, head and neck cancer, kidney cancer, and peritoneal cancer. The group always emphasizes on collaboration (both local and international) which is key to scientific breakthroughs.

The laboratory focuses on translational research of different cancer types. Examples of these works are illustrated below which illustrate the importance in working closely with practicing oncologists to correlate molecular, cellular, functional studies with clinic-pathological and follow-up information. The close collaboration between scientists and clinicians working in synergy will ensure an efficient process in facilitating breakthroughs and translating these discoveries into clinical applications. In addition, the group forms close and extensive collaboration with local and international groups, as well as with pharmaceuticals and biotechs.

Bin Tean TEH Principal Investigator MD, PhD Teh.B.T@nccs.com.sg

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Research Staff Anna H.H GAN Dachuan HUANG Ghee Chong KOO Lian Dee LER Swe Swe MYINT Choon Kiat ONG Pauline ONG Chao-Nan(Miles) QIAN Ee Yan SIEW Hwei Ling TAN Bernice WONG Willie S.S YU


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Kidney Cancer Through molecular profiling, several potential therapeutic targets in different types of kidney cancer have been identified (Furge et al., Lancet Oncol, 2010). Very recently, collaboration with the Cancer Genome Program of the Sanger Institute, UK, and the Van Andel Research Institute, USA, has led to the identification of the SWI/SNF chromatin remodeling complex gene PBRM1 as a second major gene in the most common type of kidney cancer (i.e., clear cell renal cell carcinoma), with truncating mutations in 41% (92/227) of cases (Varela I et al., Nature, in press). These findings, together with our previous report on the identification of a group of histone modifiers (UTX, JARID1C and SETD2) being mutated in the same cancer (Dalgliesh GL et al., Nature, 2010) further confirm the important role of chromatin remodeling enzymes in ccRCC. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology. Further molecular and cellular studies are underway to elucidate the mechanistic roles these ccRCC genes play in the tumorigenesis of ccRCC. Our group at the Van Andel Research Institute has recently published studies how a popular drug, sunitinib, acts on renal cell carcinoma (Huang D et al., Cancer Res, 2010) and why a significant number of patients develop resistance after a period of usage (Huang D et al., Cancer Res, 2010). The group is currently testing the effects of several novel drugs to establish their effects in overcoming this resistance. In addition, the group continues to explore the molecular mechanism of drug resistance in kidney cancer.

Bile Duct Cancer Bile duct cancer or cholangiocarcinoma is an aggressive cancer without effective therapy. It is also endemic in certain parts of South East Asia, particularly in the north east region of Thailand where the disease is considered a long-term outcome of chronic liver fluke-related infestation through local dietary habits. In collaboration with the University of Khon Kaen, the group has been studying this cancer by focusing on its genome and drug screening for affordable and effective drugs. Through molecular profiling, the group has identified the molecular signatures of this cancer. One of them, MAPKinase 13, has been found to be frequently overexpressed and serves as both a diagnostic and potential therapeutic target (Tan FL et al., Int J Cancer, 2010). As most of these patients come from low-income families in society, we also plan to undertake high-throughput screening for affordable and effective drugs by focusing on off-label, FDA approved drugs that have run out of their patency.

T-cell lymphoma In working closely with Drs Lim Soon Thye and Tan Soo Yong, a lymphoma translational research group has been established. The group consists of practicing oncologists, pathologists and scientists throughout the country and has extensive international collaborations. It is now a member of the National Cancer Institute (USA) TCGA (The Cancer Genome Atlas) lymphoma program. By molecular profiling and immunohistochemistry, the group has recently identified a novel biomarker for Type II enteropathy associated Tcell lymphoma, a rare but very aggressive lymphoma (Tan S-Y et al., Leukemia, in press). Further validation studies to discover additional novel biomarkers for different subtypes of T-cell lymphoma are currently underway. In addition, the group is generating lymphoma cell lines and model systems to screen for effective therapeutic agents.

Selected Publications Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin M-L, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Richard S, Kahnoski RJ, Anema J, Tuveson D, Perez-Mancera P, Mustonen V, Fischer A, Adams DJ, Rust A, Chanon W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA Exome sequencing identifies frequent mutation of the SWI/SNF complex gene, PBRM1, in renal carcinoma. Nature (2010) In press (cocorresponding author). Tan S-Y, Ooi A-S, Ang M-K, Koh M, Wong J-C, Dykema K, Ngeow J, Loong S, Gatter K, Tan L, Lim L-C, Furge K, Tao M, Lim S-T, Loong F, Cheah PL, Teh BT Nuclear expression of MATK is a novel marker of type II enteropathy associated T-cell lymphoma. Leukemia (2010) In press. Furge KA, Mackeigan JP, Teh BT Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new. Lancet Oncol. (2010) 11(6):571-578. Dalgliesh GL, Furge K, Greenman C, Chen L, Bigness G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature (2010) 463(7279):360–363 (cocorresponding author). Huang D, Ding Y, Li Y, Luo WM, Zhang ZF, Snider J, Vandenbeldt K, Qian CN, Teh BT Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma. Cancer Research (2010) 70(3):1053–1062. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Research (2010) 70(3):1063–1071.

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Clinical Trials – bringing new medicines and new hope to our patients. CTE provides a centralized service to perform these trials.


Division of

Clinical Trials and Epidemiological Sciences


CLINICAL TRIALS OFFICE

Cancer is a major health problem worldwide. About 10 million people annually are diagnosed with this disease and six million are expected to die from it. In Singapore the crude cancer incidence rate is expected to rise for the next two decades as the baby boomers now reach the age when most cancers develop. Unfortunately, despite the best efforts, we are still unable to cure most patients with recurrent cancer. Hence, search for new therapies, is critical for the cure of cancer, for the prolongation and the improvement of quality of life. These therapies are developed through clinical trials, which involve regulated and closely-monitored processes of testing new drugs and drug combinations in humans, so as to evaluate and confirm their efficacy and safety. The Clinical Trials Office of the Humphrey Oei Institute of Cancer Research provides the infra-structural support for the conduct of all phases of clinical trials at the National Cancer Centre Singapore.

We have a team of dedicated staff to support investigators in areas such as trial co-ordination, budget and project planning, protocol development, negotiation of agreements, ethical and regulatory submissions, case report form design and data discrepancy management.

Research Experience We have more than 16 years of experience in conducting clinical trials and to date, have completed over a hundred clinical trials. Currently we have about 100 ongoing trials. Of particular interests are trials of the new small molecular targeted agents, vaccines, stem-cell mini-transplants and adoptive T cell therapies on the different cancers types such as breast, lung, nasopharynx, stomach, colorectum and liver cancers. Our investigators are constantly in search of new methods and treatments, and actively coming up with new ideas and protocols for clinical testing.

Joseph WEE Head, Division of Clinical Trials & Epidemiological Sciences FAMS, MBRS, FRCR trdwts@nccs.com.sg

Ai Lin LOW Senior Manager BSc (Pharm)(Hons) ctelal@nccs.com.sg

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Research Staff Jia Ling CHEONG Ai Mee CHUA Michellore T DANNUG Kathleen Garcia DAVID Carreon Sharleen ESGUERRA Win Win HAN Genevieve HON Htar Htar HWE Ruth KHOO Wen Ya K KHOO Emily LIM Li Shan LOW Maria Carlota F MACAPAGAL Su Mon MYAT Zar Yar MYINT Yin Yin Pyone NANG Madeline P C NG

Darice Jill NG Ru Yi ONG Armina G PILAPIL Thet Pang PHOO Noryati ABD RAHMAN Wei Yan SEH Valencia Agnes SHAH Ma Than Than SHWE Yi Hui TAN Sheila Rose Morales TAPANG Julia TOH Ma Zin Mar WAI Lan Ying WANG Mung Peng WONG Belinda P Y WOON Sook Kwan YEO Liz ZHONG


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Our Infrastructure The National Cancer Centre Singapore has obtained Federalwide Assurance from the United States Department of Health and Human Services for human subject protection. This certification allows NCCS to qualify for US Government supported research from CTEP of the US National Cancer Institute. Our research co-ordinators (CRC) are stringently selected to ensure that they have the aptitude, qualification and interests suitable for the work. Most of our coordinators have at least a degree in medicine, nursing, life or health sciences and have to undergo rigorous training under strict supervision. We are well equipped to carry out routine trial procedures. We have the facilities and knowledge to ensure that biological specimens for central laboratories are handled carefully under protocol prescribed conditions. NCCS also has a GMP laboratory for preparing some of our biological agents. We have dedicated Clinical Trial Pharmacists. The Ambulatory Care Unit nurses play an active role as part of the study team to ensure that the administration and handling of study drugs are performed according to the protocol. We are also involved in research areas such as DCE-CT and DCE-MRI. PET and SPECT are available in the campus, and the Nuclear Medicine Department has its own in-house radio-chemist. We also work closely with the Singhealth Investigational Medicine Unit, which has a 30-bed inpatient unit for early phase trials. We use the Oracle Clinical Data Management System to manage data. Our team includes a trained system analyst, data management co-ordinators and statisticians.

Future Direction We aim to continue to provide a centralised service for investigators and industries to conduct clinical trials.

Selected Publications LIM WT, Tan EH, Toh CK, Hee SW, Leong SS, Ang PCS, Wong NS, Chowbay B Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (GenexolPM) in patients with solid tumors. Ann. Oncol. (2010) 21(2):382-8. Leong SS, Fong KW, Lim WT, Toh CK, Yap SP, Hee SW, Tan EH A phase II study of induction gencitabine and vinorelbine followed by concurrent vinorelbine and radiotherapy in locally advancednon-small cell lung cancer. Lung Cancer (2010) 67(3):325-9. Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and IV vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment for advanced non-small cell lung cancer. Ann. Oncol. (2009) 20(7):1249-1256. Loong SL, Hwang JS, li HH, Wee JT et al. Negligible or weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomised trial between radiation alone versus concurrent chemoradiation (SQNP-01). Radiat. Oncol. (2009) 4(1):23. Wang A, Lal S, Sandanaraj E, Lim WT, Leong SS, Tan EH, Chowbay B Phase I dose finding study of GenexelPM in Asian cancer patients. J. Clin. Oncol. (2008) 26:621s (Abstr 13512). Yap SP, Lim WT, Foo KF, Hee SW, Leong SSm Fong KW, Eng P, Hsu, AA, Wee JTS, Agasthian T, Koong HN, Tan EH Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatin combination followed by surgery in locoregionally advanced NSCLC – Asian experience. Ann. Acad. Med. Singapore (2008) 37(5):377-82. Leong SS, Wee J, Rajan S, Toh CK, Lim WT, Hee SW, Tay MH, Poon D, Tan EH Triplet combination of gemcitabine, paclitaxel and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharygeal carcinoma. Cancer (2008) 113(6):1332-1337. Wong ZW, Ang PC, Chowbay B, Wong NS, See HT, Khoo KS Phase I / II trial of gemcitabine with pegylated liposomal doxorubicin as firstline therapy in Asian women with metastatic breast cancer. Breast (2008) 17(5):517-22.

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BIOSTATISTICS UNIT

The Biostatistics and Epidemiology Unit primarily provides statistical and epidemiological support for clinical trials and other studies conducted at the National Cancer Centre Singapore. This is in the form of consultations, collaborations as well as teaching. We also initiate and engage in relevant areas of applied biostatistics and epidemiology research.

The conduct of good biomedical research requires the appropriate disease expertise and rigorous research methodology combined with strong quantitative analyses. The added value of statistical techniques to biomedical research is well recognised. In biomedical studies the correct design, analysis and interpretation of the study all require the development and application of good statistical methods. While many such techniques have already been developed, only a relatively small number of these are routinely used in practice. A key reason for this is that many of these methods have not made the transition from the ‘statistical lab’ to the clinic. However, these methods may potentially help improve all aspects of the biomedical research process, ultimately resulting in more accurate conclusions being drawn e.g. regarding the usefulness of new treatments. This has important ethical implications as patients consent to have their data used for biomedical research with the expectation that the information that they provide will be used in the most optimal way to provide benefits for future patients and potentially themselves as well. Research thus needs to be carried out to test and bring better biostatistical and clinical research methodologies into clinical practice. Moreover, there are many problems in biomedical research for which better (albeit less well known) statistical methods could be employed, to allow for a better analysis and interpretation of the data. This can be achieved through the conduct of applied biostatistics research and teaching. Some of the projects currently engaged include cancer epidemiology modeling, clinical trial methodology, applications of Bayesian statistics in medicine and applications of statistics in genetics. The Biostatistics Unit also provides expert biostatistics support for all clinical trials and related studies conducted at the National Cancer Centre Singapore.

Tam Cam HA Senior Epidemiologist Epidemiologist-in-charge PhD ha.tam.cam@nccs.com.sg

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Director, Biostatics and Quantitative Epidemiology, Singhealth Adjunct Associate Professor, Department of Epidemiology and Public Health, YLL School of Medicine, NUS

Say Beng TAN Principal Biostatistician MA, MSc, PhD, CStat ctetsb@nccs.com.sg

Adjunct Associate Professor, Department of Biostatistics and Bioinformatics, Duke University

Joint Appointments: Senior Vice President & Chief Scientific Officer Singapore Clinical Research Institute

Fei GAO Adjunct Principal Investigator MSc, PhD ctegfe@nccs.com.sg

Associate Professor and Director, Centre of Quantitative Biology and Medicine, Duke-NUS Graduate Medical School.

Research Staff Wallace CHEN Xuan HOU Whee Sze ONG Sze Huey TAN


EPIDEMIOLOGY UNIT

National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

The primary objective of the Epidemiology Unit is to conduct clinical translational research to investigate the risk factors for cancer and the patterns of disease in the wider population at large. This provides a platform for the development of studies to investigate possible interventions to increase survival and reduce the incidence of cancer or the stage at which the disease is diagnosed. As new technology becomes available, such as the ability to detect molecular biomarkers, better treatment outcomes for patients will also become available. The design and conduct of scientifically sound epidemiological studies is important in ensuring quality results for the future benefit of all patients. The conduct and provision of epidemiological research is able to provide direct clinical applications for patient care. Almost all aspects of medical research require the use of statistical and epidemiological techniques at some point of the research process. Inefficient or erroneous methodology could have severe consequences on the interpretations of the research findings. This could eventually result in patients having less than optimal or worse still, inappropriate treatment. The unit applies principles of evidence-based medicine when designing studies to ensure that the most feasible study has been conducted. A variety of studies are currently being investigated including studies in genetic epidemiology, screening and cancer risk factors. With collaborations both locally and internationally, the unit aims to investigate population risk factors for cancer.

Selected Publications Li H, Ha TC, Tai BC XRCC1 Gene Polymorphisms and Breast Cancer Risk in Different Populations: A Meta-Analysis. The Breast (2009) 18(3):183-91. Machin D, Campbell M, Tan SB, Tan SH Sample Size Tables for Clinical Studies. 3rd Edition. Wiley-Blackwell (2009). Gao F, Ng GY, Cheung YB, Thumboo J, Pang G, Koo WH, Sethi VK, Wee J, Goh C The Singaporean English and Chinese versions of the EQ-5D achieve measurement equivalence in cancer patients. J. Clin. Epidemiol. (2009) 62(2):206-213. Gao F, Tan SB, Machin D, Wong NS Confirmation of double-peaked time distribution of mortality among Asian breast cancer patients in a population-based study. Breast Cancer Research (2007) 9(2):R21. Ha TC, Li H Meta-analysis of Clodronate and Breast Cancer Survival. British Journal of Cancer (2007) 96(12):1796-1801. Li H, Tai BC RNASEL gene polymorphisms and the risk of prostate cancer: a meta-analysis. Clinical Cancer Research (2006) 12(19):5713-5719.

Tam Cam HA Senior Epidemiologist Epidemiologist-in-Charge PhD ha.tam.cam@nccs.com.sg Joint Appointments: Assistant Professor and Course Director, Investigative Methods and Tools, DUKE-NUS Graduate Medical School Research Staff Grace Sook Kwin YONG

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Clinician Investigators and Scientists


DEPARTMENT OF MEDICAL ONCOLOGY

Oncology Research Groups: • Breast • Gynae-oncology • Gastrointestinal • Lymphoma • Thoracic and Head & Neck • Urologic • Early Clinical Research Unit (ECRU)

Breast Oncology Research Clinician Scientists:

Soo Kien LO Raymond NG Yoon Sim YAP

Nan Soon WONG Senior Consultant, Department of Medical Oncology Director, Public Education & Patient Support MBBS, MMed (Internal Medicine), MRCP (UK) dmowns@nccs.com.sg

Specific Projects: 1) Role of carboplatin as neoadjuvant chemotherapy for triple negative breast cancer 2) Feasibility and efficacy of a non-anthracycline regimen as neoadjuvant therapy for locally advanced breast cancer incorporating docetaxel pharmacokinetic and pharmacogenomic studies 3) Efficacy of metronomic chemotherapy in combination with aromatase inhibitors in metastatic breast cancer correlating response with circulating endothelial progenitor cell levels 4) Impact of CYP2D6 polymorphisms on tamoxifen metabolism in Asian women 5) Establishment of repository of clinically annotated core biopsies from metastatic sites at time of tumour progression or recurrence, or prior to neoadjuvant therapy for future gene expression profiling to explore predictive markers of treatment sensitivity and resistance

Han Chong TOH Senior Consultant & Head, Department of Medical Oncology Principal Investigator, Laboratory of Cell Therapy and Cancer Vaccine BSc(Lond), MBBChir(Camb), MRCP(UK), FRCP(Edin), FAMS dmothc@nccs.com.sg

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Selected Publications Gynae-oncology Research Clinician Scientists / Collaborators: Immunotherapy : Dr Han Chong TOH, Dr Marissa TEO, Dr Peter WANG, Dr Giogia PASTORIN, Dr Rod DUNBAR, Dr Albert DEISSEROTH, Dr Stephen GOTTSCHALK Inflammation and Cancer : Dr Han Chong TOH, Dr Raghib ALI, Dr Simon ONG, Dr Chee Kian THAM, Dr R. SIM, Dr G. LOPES (and other regional collaborators)

John W.K. CHIA Consultant, Department of Medical Oncology MBBS, MMed (Internal Medicine), MRCP (UK) nmocwk@nccs.com.sg

Gynaecology : Dr LT SOH, Dr Lynette NGO, Dr YN CHIA, Dr YK LIM, A/Prof TH HO, A/Prof SK TAY, Dr Cindy PANG, Dr Elisa KOH, Dr Ivy CHEW, Dr SH CHEW, Asst Prof LK GOH, A/ Prof The Hung HUYNH , Prof Bin Tean TEH Areas of Clinical Research: Immunotherapy for Solid Tumors, Inflammation and Cancer, Gynaecological Malignancies Specific projects: 1) Dendritic Cell vaccine (Ad5F35-dLMP1-LMP2) for Metastatic Nasopharyngeal Cancers 2) Adoptive T cell therapy with EBV specific Cytotoxic T Lymphocytes for Nasopharyngeal Cancers 3) MUC1-CD40L vaccine for MUC1 expressing tumors 4) EBV peptide vaccination strategies for Nasopharyngeal Carcinoma 5) ASCOLT study – Adjuvant Aspirin for Dukes B and C Colorectal cancers 6) Mutational and Immune analysis of Gynaecological Tumors 7) Prognostic classifiers for Leiomyosarcoma of the Uterus

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Breast Oncology Research Gastrointestinal Oncology Research Clinician Scientists:

Han Chong TOH(Head of DMO) Wen Hsin KOO (Deputy Director, NCCS) Simon ONG (Director of Education, NCCS) Hwee Yong LIM Joanne NGEOW Chee Kian THAM Su Pin CHOO Consultant, Department of Medical Oncology BMBS (Nottingham), MRCP(UK) choosupin@nccs.com.sg

The Gastrointestinal (GI) Cancer team of the Department of Medical Oncology (DMO) consists of a group of highly specialized medical oncologists who treat malignancies of the gastrointestinal system and who are actively involved in translational and clinical research. Our clinical services also include hyperthermic intraperitoneal chemotherapy and management of neuro-oncology cancers. Our team’s mission is to provide top-notch cancer care to our patients using the most advanced medical therapies, and providing opportunities for our patient to participate in clinical trials, with the ultimate aim of prolonging survival and improving quality of life. Core to this is our emphasis on doing research to develop new therapies for patients and to enhance our understanding of GI cancers and involvement in education of doctors, nurses, allied health and the public. Our GI cancer database links high quality clinical data to patient clinical samples, allowing us fruitful collaborations with laboratory scientists to answer key scientific questions in GI oncology and develop a better understanding of GI cancers in our population. We have numerous investigator-initiated and pharmaceutical-sponsored clinical trials investigating novel therapeutics and treatment approaches. We have at least 20 ongoing trials at any point in time. We also have special interests in immunotherapy and cancer genetics. Two examples of our Bench-to-Bedside Research projects that are actively recruiting patients include: 1) Phase II study of Genomic-guided standard-of-care chemotherapy for advanced gastric cancer. This is a proof of concept study based on our laboratory colleagues’ preclinical work demonstrating that gastric cancer cell lines stratified by their molecular signature exhibited differential sensitivity to oxaliplatin and cisplatin. This trial is done in collaboration with National University Hospital and Yonsei Cancer Centre Korea. 2) A phase I/II study of AZD6244 in combination with Sorafenib in Advanced Hepatocellular Carcinoma. The rationale from this study came about from pre-clinical work with our laboratory collaborators which showed that the addition of AZD6244 enhanced the anti-tumour effect of sorafenib in HCC xenograft models. This trial also involves National University Hospital and is a joint collaboration with Astra-Zeneca.

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Lymphoma Oncology Research Clinician Scientists:

Miriam TAO Kevin TAY Richard QUEK The Lymphoma Translational Research Laboratory: Soon Thye LIM Senior Consultant & Deputy Head, Department of Medical Oncology MBBS, MRCP(UK) dmolst@nccs.com.sg

Our laboratory is focused on the molecular mechanisms of lymphoid malignancies. Currently, epidemiological, clinical and molecular data on malignant lymphomas among Asians is limited and an increasing body of information from our center and others suggest that geographic localities as well as ethnicity are important factors in lymphomagenesis. The main aims of this laboratory are: 1. To exhaustively evaluate the molecular characteristics of lymphoma, particularly subtypes that occur at higher frequencies in Asians. 2. To develop new biomarkers, treatment targets and novel treatment strategies, particularly against lymphoma subtypes uniqueto Asians. 3. To provide molecular correlation to lymphoma clinical trials. Our laboratory takes advantage of the large clinical and pathological data and material available to our researchers. Integrating the clinical and pathological data of our patients together with the molecular and genomic information derived from this laboratory, it allows us to identify predictive and prognostic biomarkers as well as potential therapeutic targets for novel treatment.

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Thoracic and Head & Neck Oncology Research Clinician Scientists:

Mei-Kim ANG Darren LIM Quan Sing NG Daniel TAN Thoracic and Head & Neck Oncology Research Eng Huat TAN Senior Consultant, Department of Medical Oncology MBBS, MMed(Internal Medicine), MRCP(UK), FAMS dmoteh@nccs.com.sg

The thoracic and head/ neck oncology team has maintained a strong track record in running clinical trials from phase I to III. Initial epidemiologic studies established the unique clinical phenotype of our lung cancer patients, and the group has subsequently developed trials aimed at defining new treatment standards for specific clinical subgroups. With improved delineation of distinct molecular subtypes of cancer, our research efforts are focused at understanding the biology of each tumour to enable development of rational therapeutic strategies. This is especially true in the era of targeted therapeutics and the more widespread application of genomics in the clinic. One of the current challenges is the implementation of molecular tests that define patient populations that may be more amenable to specific treatments – ranging from EGFR mutations and ALK translocations in lung cancer to HPV positive or negative oropharyngeal cancers, and XRCC1 status in head and neck cancers. These efforts are being developed in conjunction with the Pathology Department (Tan PH, Takano A, Hwang J) and will enable more directed strategies that address underlying disease biology. Similarly one of the areas of interest is the development of approaches to overcome resistance to EGFR TKIs, where novel agents targeting HGF-Met axis and PI3K inhibitors are now specifically set up for this patient group. Biomarkers that provide earlier readouts of drug effect are also increasingly applied to clinical trials, such as the use of functional imaging in a pazopanib monotherapy trial in nasopharyngeal cancer, and examining circulating endothelial progenitor cells and functional imaging in a lung cancer trial combining sorafenib and metronomic vinorelbine (PI: Tan EH). Future directions include developing real time electronic capture of clinical information at point of care, and incorporating medium throughput screening for somatic mutations using the Sequenom platform and minimally invasive biomarker platforms like circulating tumour cells.

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Urologic Oncology Research Clinician Scientists:

Noan-Minh CHAU

Min-Han TAN Consultant, Department of Medical Oncology MBBS (Singapore), MRCP (UK) tan.min.han@nccs.com.sg

The National Cancer Centre Singapore is an international centre for research in prostate, renal, testicular and bladder cancer. Many leading trials in genitourinary cancer are conducted here, which allow us to apply novel leading anti-cancer compounds for the immediate use of our patients in a research setting. For example, cabazitaxel, newly approved by the FDA in late 2010 for its effectiveness in prostate cancer, was available to our patients on a research basis at the NCCS since 2006. Many such novel agents are in clinical research settings for our patients. In addition to trials, our extensive translational research activities in urologic oncology also focuses on molecular correlates, such as circulating tumor cells, high-throughput expression and single nucleotide polymorphism genomic profiles and candidate predictive serum proteins. Specific outcomes of interest include drug response and prognostic outcomes (in collaboration with Prof Tan Puay Hoon, Prof Christopher Cheng and Prof Weber Lau of SGH, Prof Teh Bin Tean and Prof Balram Chowbay of NCC, Prof. Lim Chwee Teck and Dr. Sng Jen Hwei of NUS). These studies are only possible with extensive collaborations and combined databases between the disciplines of urology, pathology, medical oncology and radiation oncology. The NCCS has a group of clinicians and researchers focusing on cancer genetics, in terms of clinical care and basic research. Patients with hereditary cancer syndromes receive specialized clinical care, and are involved in translational research. The NCCS hosts a von Hippel-Lindau Clinical Care Center of Excellence. Additionally, epidemiologic research on statistical modelling of prognostic outcomes in urologic cancers is also conducted. Memberships/Affiliations: a) Dr. Tan Min-Han is a member of the International Metastatic Renal Cell Carcinoma Consortium since 2009. b) Dr. Tan Min-Han is a member of the Cochrane Prospective Meta-Analysis Methods Group (Prostatic Diseases and Urologic Cancers Group). c) Dr. Tan Min-Han leads the von Hippel-Lindau Clinical Care Center of Excellence.

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EARLY CLINICAL RESEARCH UNIT (ECRU)

ECRU Workgroups/Collaborators: Noan Minh CHAU (Urologic) Su Pin CHOO (Director, Gastrointestinal) Quan Sing NG (Functional Imaging) Richard QUEK (Sarcoma/Rare Tumours) Daniel TAN (Lung/ Head/Neck) Eng Huat TAN (Director of Research, DMO) Nan Soon WONG (Breast/ Gynae) Chowbay BALRAM (PK/PD lab) Samantha LEE (Administrative coordinator) Lan Ying WANG (CRC Team Leader) Lishan LOW Zhong Li LIZ Zin MA Sook Kwan YEO ECRU is a unit within the department of Medical Oncology that was officially established on 16th October 2009. The unit was formed with an academic focus to enhance support for early phase (Phase 0/1/2) clinical trials and investigator-initiated trials. ECRU provides a one-stop-shop for the conduct of early phase clinical trials with a core team of clinical research coordinators (CRC) and assistant research coordinators. It works in close collaboration with other clinicians and research laboratories to consolidate capabilities and ensure seamless trial conduct with an emphasis on accelerating throughput of correlatives studies by matching investigator with collaborators. The mission of ECRU is to bring new and novel agents to the patient’s bedside and develop new therapeutic options for cancer patients through investigator-initiated scientifically driven research.

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National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Examples of current ECRU studies include:

Selected Publications

1) A Prospective Study of Metronomic Oral Vinorelbine in Combination with Sorafenib in Advanced Non-small Cell Lung (PI: Dr Tan Eng Huat) a) A phase I dose-finding study of the combination of metronomic oral vinorelbine and sorafenib b) Pharmacokinetics profiling of the combination of metronomic oral vinorelbine and sorafenib at maximum-tolerated dose (MTD)

Tan MH, Mester J, Peterson C, Yiran Y, Chen J, Rybicki LA, Milas K, Pederson H, Orloff MS, Eng C A proposed clinical scoring system for selection of patients for PTEN mutation testing based on prospective cohort analysis of 3,042 probands. Am J Hum Genet (2011) In press.

2) A Safety and Tolerability Study of RAD001 (mTOR inhibitor) in Combination with Two Dosing Schedules of LBH589B (histone deacetylase inhibitor) in Solid Tumors/Lymphomas with Enrichment for EBV-Driven Tumors (PI: Dr Daniel Tan) 3) A Phase 2 Study of trastuzumab in Combination with TS-ONE and cisplatin in first-line human epidermal growth factor receptor 2 (HER2)positive advanced gastric cancer (PI: Dr Choo Su Pin) 4) A Phase 1 Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) (PI: Dr Darren Lim) 5) Aspirin for Dukes C and high risk Dukes B colorectal cancers: an international, multi-centre, double blind, randomised placebo controlled phase III trial (PI: Dr John Chia) 6) Clinical Validation of a Microfluidic Device for Isolation and Molecular Characterization of Circulating Tumor Cells (CTC) (PI: Dr Darren Lim) 7) CYP2D6 Pharmacogenetics and Its Influence on Tamoxifen Pharmacokinetics and Clinical Outcome in Asian Breast Cancer Patients (PI: Dr Wong Nan Soon)

Heng DYC, Park T, Bjarnason GA, Vaishampayan U, Tan MH, Knox J, North S, Kollmannsberger C, McDermott DF, Rini BI, Choueiri D Progression-free survival (PFS) as a predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with contemporary targeted therapy. Cancer (2010) In press. Ngeow J, Lim WT, Leong SS et al. Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma. Ann. Oncol. (2010) Epub ahead of print. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J. Hepatol. (2010) 52(1):79-87. Lim WT, Tan EH, Toh CK et al. Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (GenexolPM) in patients with solid tumors. Ann. Oncol. (2010) 21(2):382-388. Tan IB, Ang KK, Ching BC, Mohan C, Toh CK, Tan MH Testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults : a meta-analysis and systematic review. Cancer (2010) 116(19):4520-32. Tan EH, Ramlau R, Pluzanska A et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann. Oncol. (2010) 21(2):193-4. Tham CK, Choo SP, Poon DY, Toh HC, Ong SY, Tan SH, Wang ML, Foo KF Capecitabine with radiation is an effective adjuvant therapy in gastric cancers. World J. Gastroenterol. (2010) 16(29):3709-15. Toh CK, Ahmad B, Soong R et al. Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas. J. Thorac. Onco. (2010) 5(1):17-22. Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, Phoon YP, Soe Y, Tan SH, Hee SW, Foo KF, Ong S, Koo WH, Zocca MB, Claesson MH Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients. Clin. Cancer Res. (2009) 15(24):77267736. > 71


DEPARTMENT OF SURGICAL ONCOLOGY

The Department of Surgical Oncology was established as part of NCCS’ strategic vision to be the premier academic surgical center in the Outram campus to deliver specialized cancer surgery. The surgical services are divided into well-established sub-specialities with specific focus on hepatobiliary, thoracic, breast, head and neck, colorectal and upper GI malignancies. Apart from providing site-specific expertise, the department is also committed to the other two pillars of NCCS, i.e. teaching and research. Our research activities include clinical and laboratory-based projects. Clinical research runs the gamut from data audits, retrospective analyses and clinical trials to multi-centre phase III trials. Laboratory-based investigations are focused on translational research initiatives, either headed by surgeon-investigators in the department or in collaboration with scientists in NCCS or in other institutes at the Outram Campus.

Heng Nung KOONG Senior Consultant & Head, Department of Surgical Oncology MBBS, MMed (Surgery), FRCSEd, FAMS dsokhn@nccs.com.sg N Gopalakrishna IYER Associate Consultant, Department of Surgical Oncology Principal Investigator, Wee Kim Wee Laboratory of Surgical Oncology MBBS(Hons), FRCS(Gen), FAMS, PhD (Cambridge) gopaliyer@nccs.com.sg Kong Wee ONG Consultant, Department of Surgical Oncology MBBS, FRCS(Edinburgh), PhD(Bristol), FAMS nsookw@nccs.com.sg

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Hiang Khoon TAN Senior Consultant, Department of Surgical Oncology Co-Investigator, Wee Kim Wee Laboratory of Surgical Oncology MBBS(Singapore) ,FRCS(Edin), PhD Tan.H.K@nccs.com.sg Melissa TEO Consultant, Department of Surgical Oncology MBBS, MMed (Surg), FRCS (Edinburgh), FAMS, MPH (Johns Hopkins) nsotcc@nccs.com.sg


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Clinical and translational research initiatives: 1. Head and neck squamous cell carcinoma and nasopharyngeal cancers (led by Dr Gopal Iyer and Dr Tan Hiang Khoon) Clinical research includes establishment of the head and neck cancer database, retrospective analyses of outcome and factors predictive of outcome in our patients with head and neck cancer and clinical trials. We have recently initiated a phase 3 multi-centre trial that include participants formed over 20 institutions in 11 countries (Phase III, doubleblind, placebo-controlled study of post-operative adjuvant concurrent chemo-radiotherapy with or without nimotuzumab for stage III/IV head and neck squamous cell cancer). The translational research program for this section is led by Dr Gopal Iyer in the Wee Kim Wee Laboratory of Surgical Oncology. 2. Peritoneal metastases program (led by Dr Melissa Teo) This is a niche research area as there are few institutions locally or regionally with the surgical expertise to perform peritonectomies. Apart from surgical expertise, together with the department of medical oncology we have ample clinical experience on the subject and have an interest to identify prognostic markers, carcinogenic pathways and novel therapeutic targets that can be used for these cancers. Our research focus is targeted towards peritoneal metastases from ovarian, colorectal or primary peritoneal origin. Our research activities include: a. Clinical database for patients who undergo metastatectomy for peritoneal metastases b. Retrospective analyses to identify factors that predict outcome and prognosis for peritoneal metastases based on clinico-pathologic and imaging criteria c. Molecular profiling of these tumors to identify potential biomarkers and therapeutic targets (in collaboration with Prof Teh Bin Tean) d. Establishment of cell-line and xenograft models to understand the biology of disease (in collaboration with Prof Teh Bin Tean and Prof Huynh The Hung) 3. Soft-tissue sarcoma (led by Dr Melissa Teo) These projects have been driven by our increasing volumes of patients with soft-tissue sarcomas, especially patients with central/trunk softtissue sarcomas. They include: a. Clinical database for patients who undergo surgery for soft-tissue sarcomas and retrospective analyses to identify factors that predict outcome and prognosis for peritoneal metastases based on clinico-pathologic and imaging criteria (Dr Lee Ser Yee) b. Molecular profiling of these tumors to identify potential biomarkers and therapeutic targets (in collaboration with Drs Richard Quek and Prof Teh Bin Tean)

SelectedPublications Publications Selected NG Iyer, A Kumar, I Nixon, F Palmer, M Whitcher, SG Patel, RM Tuttle, AR Shaha Incidence and Significance of Delphian node metastasis in papillary thyroid cancer. Ann Surg (2010) In press. Iyer NG, Clark JR, Singham S, Zhu J Role of pretreatment 18FDG-PET/CT in surgical decision-making for head and neck cancers. Head Neck (2010) 32(9):1202-8. Tan HK, Giger R, Auperin A, Bourhis J, Janot F, Temam S Salvage surgery after concomitant chemoradiation in head and neck squamous cell carcinomas - stratification for postsalvage survival. Head Neck (2010) 32(2):139-47. Ong KW, Teo M, Lee V, Ong D, Lee A, Tan CS, Vathsala A, Toh HC Expression of EBV latent antigens, mammalian target of rapamycin, and tumor suppression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications. Clin. Cancer Res. (2009) 15(17):5350-8. Tan BK, Tan LK, Yu K, Tan PH, Lee M, Sii LH, Wong CY, Ho GH, Yeo AW, Chow PK, Koong HN, Yong WS, Lim DT, Ooi LL, Soo KC, Tan P Clinical validation of a customized multiple signature microarray for breast cancer. Clin. Cancer Res. (2008) 14(2):461-9. Teo MC, Tan YM, Chung AY, Chow PK, Cheow PC, Soo KC, Hee SW, Ooi LL Metastectomy for non-colorectal, nonneuroendocrine liver secondaries. ANZ J. Surg. (2006) 76(7):575-8.

4. Breast cancer (led by Dr Ong Kong Wee) Breast cancer is one of the commonest malignancies treated at NCCS, with increasing incidence in our population. Furthermore, there are differences in the epidemiology of these disease not seen in the Western population, which have led many to believe that the “Asian breast cancer’ may be a variant, with differing outcome and response to therapy. Our research activities complement the various initiatives in the center, principally through meticulous collection of tumor tissue during surgery with matched and annotated databases, updated during the multidisciplinary tumor board meetings held weekly. Other projects include: a. Retrospective analyses to identify factors that predict outcome and prognosis for peritoneal metastases based on clinico-pathologic and imaging criteria b. Molecular profiling of these tumors to identify potential biomarkers and therapeutic targets (in collaboration with Drs Benita Tan and Prof Patrick Tan) > 73


DEPARTMENT OF RADIATION ONCOLOGY

Radiation Oncology (then Therapeutic Radiology) was the first department to be formed as the backbone to cancer care in the Singapore General Hospital. It has since then grown and established itself as an integral part of the National Cancer Centre Singapore. Traditionally seen as a busy service orientated department, the changing landscape of medicine and evolution of NCCS into an academic centre has seen research and teaching emerge to take an important role in our department today. Radiation Oncology is pursuing research on multiple fronts looking into various aspects such as Radiation technology, Radiobiology and Clinical trials.

Selected Clinical trials: A randomised phase II/III study of concurrent cisplatin-radiotherapy with or without induction chemotherapy using Gemcitabine, Carboplatin and Paclitaxel (GCP) in locally advanced nasopharyngeal cancer (NPC) The objective of this trial is to assess the 5 year overall survival in patients with locally advanced NPC treated with concurrent cisplatin - RT with or without induction Gemcitabine, Carboplatin and Paclitaxel (GCP). It seeks to build on the results of the Intergroup 00-99 as well as our own SQ NP01 trials where the benefit of radiotherapy with concurrent & adjuvant cisplatin & 5-fluorouracil for locally advanced NPC was established, by using a novel 3-drug combination used in an adjuvant setting in addition to concurrent chemo-radiotherapy. It started as a randomised phase II study (NCC 0302) studying the differences in disease-free survival curves and 2-year disease-free survival rates and has now been expanded into a phase II/III trial. Phase 1/2 randomised study of concurrent low dose metronomic cyclophosphamide and intensity modulated radiotherapy in stage 2 Nasopharyngeal Cancer Concurrent chemo radiation has been shown to improve cure rates in patients with stage III and IV NPC. However, the chemotherapy regiment has significant toxicities. In a bid to improve on the cure rates, while minimizing extra toxicities in patients with stage II NPC, we embarked on a Phase I/II trial to test the use of low dose daily (metronomic) cyclophosphamide chemotherapy concurrently with radiotherapy. This trial also seeks to look at the anti-angiogenic effect of metronomic cyclophosphamide using functional MRI scans. Phase 3 trial to assess the role of chest wall irradiation in intermediate risk breast cancer patients following mastectomy

Eu Tiong CHUA Senior Consultant and Head, Department of Radiation Oncology MBBS,DMRT,FRCR,FAMS trdcet@nccs.com.sg

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Clinician Scientists: Francis CHIN Kam Weng FONG James LEE Susan LOONG Yoke Lim SOONG Terence TAN Richard YEO Joseph WEE Fuh Yong WONG


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Postoperative radiotherapy is routinely given to patients at higher risk of recurrence (tumour size > 5cm or 4 or more lymph nodes are involved). In patients with less than four involved axillary lymph nodes or in those without lymph node involvement but have other features which increase the recurrence risks, it is not clear whether postoperative radiotherapy is needed. The SUPREMO trial aims to establish the benefits of postoperative radiotherapy to the chest wall in these patients who are at intermediate risk of recurrence. Through this randomized controlled trial, we aim to provide level I evidence to offer post mastectomy radiotherapy to all patients at intermediate risk of recurrence or not at all, thence sparing women the time and expense of an unnecessary treatment and avoid the potential hazards from radiation exposure. Feasibility study using Intensity Modulated Radiation Therapy (IMRT) with concurrent use of temozolomide for Glioblastoma Multiforme (GBM) Glioblastoma Multiforme (GBM) is the most commonly occurring primary brain tumour in adults. Post-operative radiotherapy to the tumour bed following gross total resection of GBM improves local control and survival. However, local recurrence remains the most common pattern of failure. Because of the large volume of brain irradiated, escalation of radiation doses beyond 60Gy is fraught with severe neuro-cognitive toxicity. The advent of highly conformal radiotherapy technique such as IMRT allows dose sculpting to restrict high doses to residual tumour/tumour bed while preserving as much uninvolved normal tissue as possible. Temozolomide has been demonstrated to improve survival beyond that achieved with radiotherapy alone in phase III trials. We aim to test the feasibility of the combination of IMRT and temozolomide in patients following gross tumour debulking in this single arm Phase II study. Selected Radiation technology research: Atlas Based Auto contouring of Radiation Structures. We started a research project to develop a customised atlas using our historical patient data sets to create a local atlas for site specific automatic contouring for patients slated for radiation therapy. Patients are scanned and image data sets compared with our historical patients to find a similar patient for use as a starting point for the algorithm to contour normal organs and fusion of MRI. This project has practical clinical application of greatly reducing the time required for contouring and fusion and the doctor needs only to review and adjust the contours for subsequent planning. Electron dosimetry and evaluation of the Monte Carlo algorithm at extended distances Electron dosimetry at extended distances is a challenge due to enhanced scattering conditions that may affect the accuracy of dose calculation. Extensive measurements were done to obtain relative output factors at effective source surface distances of 105cm to 120cm. This will be incorporated into a common physics database for monitor unit calculation. Work is also underway to verify a Monte Carlo algorithm against the measurement data at extended SSDs. Study of Maximum Intensity Projection (MIP) errors in 4D Computerised Tomography (CT) planning 4D CT is used in radiotherapy for tracking tumour motion. The breath cycle of each patient is unique and varied. Work is underway to understand the effects of various parameters in each breath cycle that will affect the acquisition of 4D images. In particular, the uncertainty in maximum intensity projection images will be studied using a 4D phantom.

Selected Publications Tham IW, Hee SW, Yeo RM, Salleh PB, Lee J, Tan TW, Fong KW, Chua ET, Wee JT Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapythe national cancer centre Singapore experience. Int. J. Radiat. Oncol. Biol. Phys. (2009) 75(5):1481-6. Wee JT, Anderson BO, Corry J, D'Cruz A, Soo KC, Qian CN, Chua DT, Hicks RJ, Goh CH, Khoo JB, Ong SC, Forastiere AA, Chan AT Management of the neck after chemo radiotherapy for head and neck cancers in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. (2009) 10 (11): 1086 – 92. Chua ML, Ong SC, Wee JT, Ng DC, Gao F, Tan TW, Fong KW, Chua ET, Khoo JB, Low JS Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngeal carcinoma. Head Neck (2009) 31(3):346-54. Loong SL, Hwang JS, Li HH, Wee JT, Yap SP, Chua ML, Fong KW, Tan TW Weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01). Radiat. Oncol. (2009) 4:23. Tan JSP, Chan LL, Tan KL, Lee JCL, Wan CM, Leong JL Comparison of radiation dose to the eye lens delivered by a 16-slice and 64-slice multi-detector CT (MDCT): Implications for improving patient care Am. J. Neuroradiol. (2009) 30(2):373-377. Tan WM, Paterson MC, Koo GC, Li HH, Price A, Loong SL Increased but error-prone nonhomologous end joining in immortalized lymphoblastoid cell extracts from adult cancer patients with late radionecrosis. Int. J. Radiat. Oncol. Biol. Phys. (2008) 72(1):178-85. Low WK, Toh ST, Wee J, Fook-Chong SM, Wang DY Sensorineural hearing loss after radiotherapy and chemo radiotherapy: a single, blinded, randomized study. J. Clin. Oncol. (2006) 24(12): 1904-9. Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW, Tan HS, Lee KS, Loong S, Sethi V, Chua EJ, Machin D Randomized trial of radiotherapy versus concurrent chemo radiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/ International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J. Clin. Oncol. (2005) 23 (27): 6730-38.

Selected Radiobiology Research: See “Laboratory of Genome Maintenance - Dr Susan Loong’s Laboratory”. > 75


DEPARTMENT OF PALLIATIVE MEDICINE

The Department of Palliative Medicine was established in 1999 as part of NCCS’ vision to provide holistic care for cancer from prevention and diagnosis to terminal disease. Palliative care provides expertise in symptom management and psychosocial support for patients and their families as part of the continuum of cancer care. The department provides clinical services to patients at NCCS, Singapore General Hospital, and other Singhealth institutions. It also provides visiting consultant services to hospice organisations in the community. Our research interests include validation of quality of life instruments, clinical trials, health service research and laboratory-based research. We welcome collaboration that is relevant to our current projects as well as new research projects relevant to Palliative Medicine.

Current Research Projects: Care of the Dying Coordinated Clinical Pathway (CDP) Provision of quality end-of-life care has gained prominence worldwide in recent years. The Liverpool Care Pathway for the Dying Patient has been recognised as the gold standard for end-of-life care for dying patients in UK. In a pilot project, the pathway was adapted for use in an oncology ward in SGH to improve care of the dying. Preliminary results of the pre- and post-implementation audit (n=60) show improved end-of-life care in terms of symptom control, documentation of end-of-life care as well as increased consideration towards discontinuation of non-essential monitoring prior to death. These findings were presented at the European Society of Medical Oncology Congress 2008 and the poster was accorded best poster award for its category. We have now extended the project to cover dying renal patients. Results from this are pending.

Pharmacogenetics of Opioid Receptor Genes It is clinically well established that patients respond differently to opioid analgesics such as morphine and fentanyl. Genetic variants such as single nucleotide polymorphisms (SNPs) can contribute to these differences. Establishing the molecular mechanisms underpinning the effects of genetic variants in opioid receptor genes on differences in opioid response, may help develop better opioid analgesics with maximum efficacy and minimum side effects. It may also aid clinicians in identifying patients at risk of serious or burdensome side effects so that alternative opioids may be used for these patients. These are the aims underlying the concept of personalised drug therapy for our patients.

Cynthia GOH Senior Consultant & Head, Department of Palliative Medicine,NCCS, Director, Lien Centre for Palliative Care PhD, FAMS, FRCPE, FRCP, FAChPM dpmgoh@nccs.com.sg > 76

Research Staff Lalit KRISHNA Seok Hui NEO Grace PANG Limin QU Deborah WATKINSON Yin Yee WONG Alethea YEE


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

In collaboration with the Laboratory of Liver Cancer Functional Genomics and KKH, we aim to correlate the SNPs in the opioid receptor genes with the occurrence of opioid-related phenotypes (eg morphine-induced nausea and vomiting). We have selected out potentially functional SNPs in the opioid receptor genes for further experimental validation to correlations that we may observe between the opioid receptor gene SNPs and opioid related phenotypes. Parts of these findings were presented in a poster entitled: Signature of recent positive selection at the G-allele of the “E1/A118G non-synonymous single nucleotide polymorphism in the mu opioid receptor gene� at the 5th Biologie International Pharmacogenomics Meeting in Greece 2008.

Health-related quality of life, functional status and survival of high risk End-Stage Renal Disease (ESRD) patients Little is known about the health-related quality of life (HRQoL) and functional status in our local end stage renal disease (ESRD) patients. A prospective observational study of all incident high-risk ESRD patients on dialysis or on conservative management was initiated. Outcome measures using the Kidney Disease and Quality of life (KDQoL) instrument and the Karnofsky Performance Status (KPS) were taken at intervals till 2 years post recruitment or death. Interim analysis was done on 54 patients who completed 6 months followup by 31/10/08. Results showed that for high risk ESRD patients, those who embarked on renal replacement therapy appears to have less symptoms and better overall health compared to those who chose conservative management, but there was no difference in the summary SF-36 physical or mental functioning scores. A longer period of follow-up is needed to see if these observations persist beyond 6 months. Of those who have died by 6 months, most did so within 3 months, and had a lower baseline KPS, physical functioning score and haematocrit. Forty-two (78%) patients received input from palliative care services, majority (93%) of which is hospice homecare. Of the 9 who have died by 6 months, majority passed away in hospital. However the numbers are too small to draw any conclusions at the moment. The study is expected to complete in March 2011, and final analysis of results will be done then.

Breakthrough Opioid Study Patients who take regular opioids such as morphine to relieve pain, frequently experience episodes of pain between their regular doses of medication. This is called breakthrough pain for which immediate release opioids are used. No one has defined the optimal dose of this breakthrough in relation to the background analgesia being used. Hence in collaboration with Flinders University, Australia, a double-blind, dose-ranging study was initiated to determine the optimal dose of oral morphine needed to treat breakthrough pain for people on regular opioids in the palliative care setting. The results from this study will provide an evidence base for a core element of pain management which is currently lacking.

Selected Publications Yee A, Seow YY, Tan Slt, Qu LM, Goh C, Lee G What do renal healthcare professionals in Singapore think of advance care planning for patients with endstage renal disease?. Nephrology (2010) Epub ahead of print. Krishna L, Goh C Opioid use amongst cancer patients at the end of life. Ann. Acad. Med. Singapore (2010) 39:790-97. Pang GS, Wang J, Wang Z, Goh C, Lee CG The G allele of SNP E1/A118G at the muopioid receptor gene locus shows genomic evidence of recent positive selection. Pharmacogenomics (2009) 10(7):11019. Pang GS, Wang J, Wang Z, Lee CG Predicting potentially functional SNPs in drug-response genes. Pharmacogenomics (2009) 10(4):63953. Gao F, Ng GY, Cheung YB, Thumboo J, Pang G, Koo WH, Sethi VK, Wee J, Goh C The Singaporean English and Chinese versions of the EQ-5D achieved measurement equivalence in cancer patients. J. Clin. Epidemiol. (2009) 62(2):206-13. Cheung YB, Thumboo J, Gao F, Ng GY, Pang G, Koo WH, Sethi VK, Wee J, Goh C Mapping the English and Chinese Versions of the Functional Assessment of Cancer Therapy-General to the EQ-5D Utility Index. Value Health (2009) 12(2):371-6. Cheung YB, Goh C, Thumboo J, Khoo KS, Wee J Variability and sample size requirements of quality-of-life measures: a randomized study of three major questionnaires. J. Clin. Oncol. (2005) 23(22):4936-4944. Cheung YB, Khoo KS, Thumboo J, Ng GY, Wee J, Goh C Validation of the English and Chinese versions of the Quick- FLIC quality of life questionnaire. Br. J. Cancer (2005) 92(4):668-672.

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DEPARTMENT OF ONCOLOGIC IMAGING

The Department of Oncologic Imaging is leading angiogenesis imaging research in two grants, one funded by the Singapore Cancer Syndicate (SCS-CS-0072) and another by the Biomedical Research Council (BMRC 08/1/31/19/577) to yield information about cancer blood circulation from routine CT and MRI scans.

Anti-angiogenic agents are new anticancer agents that prevent tumour growth by suppressing the growth new vessels stimulated by the cancer (angiogenesis). They often do not result in a decrease in tumour size even though the drug is efficacious. Dynamic contrast-enhanced MR imaging (DCE MRI) and computed tomography (DCE CT) have emerged as methods that can assess tumour angiogenesis and hence show drug activity. They can be performed by currently available scanners used for routine patient scanning. We hope to discover a more sensitive and accurate way of non-invasively assessing the degree of angiogenesis with the eventual goal of showing that DCE MRI and DCE CT is a biomarker of angiogenic activity. We hope to show that early assessment by DCE MRI and DCE CT after a single dose of anti-angiogenic agent, would allow clinicians to predict whether the patient would benefit from a full course. This would save patients who would not benefit from therapy the high financial costs of the new drug. We have validated blood flow calculations from our unique model (Distributed Parameter model) and have shown that parameters calculated from our model show better correlation with drug exposure of various anti-angiogenic agents. They also show promise in predicting patient outcome. Applying our model to the liver, we were able to reflect the normal as well as the tumour-induced changes in the blood circulation. The grant from BMRC focuses our research effort on the liver to try to proof that our calculated measures of blood flow and capillary permeability are accurate and to apply our model to routine day-to-day scanning so as to provide additional information about tumour circulation. The grant also allows us to apply our technique to drug trials involving liver cancer to determine if the cancer blood circulation calculations from our model can predict response early in the course of therapy.

Choon Hua THNG Senior Consultant, Department of Oncologic Imaging MBBS, FRCR dditch@nccs.com.sg

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Tong San KOH Principal Research Physicist PhD koh.t.s@nccs.com.sg


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Our model can potentially be applied to other cancers such as lymphoma, head and neck cancers and breast cancer.

Selected Publications Koh TS, Thng CH, Hartono S, Kwek JW, Khoo JB, Miyazaki K, Collins DJ, Orton MR, Leach MO, Lewington V, Koh DM Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input twocompartment model. Magn. Reson. Med. (2010) Epub ahead of print. Thng CH, Koh TS, Collins DJ, Koh DM Perfusion magnetic resonance imaging of the liver. World J. Gastroenterol. (2010) 16(13):1598-609.

Figure 1: Permeability Surface Area Product

Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, Yong WP, Chen CS, Lee SC, Wong J, Lim R, Sukri N, Lim SE, Ong AB, Steinberg J, Gupta N, Pradhan R, Humerickhouse R, Goh BC Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. J. Clin. Oncol. (2009) 27(28):4718-26. Koh TS, Thng CH, Hartono S, Lee PS, Choo SP, Poon DY, Toh HC, Bisdas S Dynamic contrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modeling. Eur. Radiol. (2009) 19(5):1184-96. Bisdas S, Rumboldt Z, Wagenblast J, Baghi M, Koh TS, Hambek M, Vogl TJ, Mack MG Response and progression-free survival in oropharynx squamous cell carcinoma assessed by pretreatment perfusion CT: comparison with tumor volume measurements. AJNR Am. J. Neuroradiol. (2009) 30(4):793-9. Bisdas S, Donnerstag F, Berding G, Vogl TJ, Thng CH, Koh TS Computed tomography assessment of cerebral perfusion using a distributed parameter tracer kinetics model: validation with H(2)((15))O positron emission tomography measurements and initial clinical experience in patients with acute stroke. J. Cereb. Blood Flow Metab. (2008) 28(2):402-11. Koh TS, Thng CH, Lee PS, Hartono S, Rumpel H, Goh BC, Bisdas S Hepatic metastases: in vivo assessment of perfusion parameters at dynamic contrast-enhanced MR imaging with dualinput two-compartment tracer kinetics model. Radiology (2008) 249(1):307-20.

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Publications


Highlighted Publications for 2007:

The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes Ovarian Cancers to Paclitaxel Ahmed AA, Mills AD, Ibrahim AE, Temple J, Blenkiron C, Vias M, Massie CE, Iyer NG, McGeoch A, Crawford R, Nicke B, Downward J, Swanton C, Bell SD, Earl HM, Laskey RA, Caldas C, Brenton JD Cancer Cell. 2007 Dec;12(6):514-27. Abstract The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan P, Liu ET, Yu Q Genes Dev. 2007 May 1;21(9):1050-63. Abstract Polycomb-repressive complex 2 (PRC2)-mediated histone methylation plays an important role in aberrant cancer gene silencing and is a potential target for cancer therapy. Here we show that S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) induces efficient apoptotic cell death in cancer cells but not in normal cells. We found that DZNep effectively depleted cellular levels of PRC2 components EZH2, SUZ12, and EED and inhibited associated histone H3 Lys 27 methylation (but not H3 Lys 9 methylation). By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, we have identified a prominent set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. We further demonstrate that the preferential reactivation of a set of these genes by DZNep, including a novel apoptosis affector, FBXO32, contributes to DZNep-induced apoptosis in breast cancer cells. Our results demonstrate the unique feature of DZNep as a novel chromatin remodeling compound and suggest that pharmacologic reversal of PRC2-mediated gene repression by DZNep may constitute a novel approach for cancer therapy. Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53 Vikhanskaya F, Lee MK, Mazzoletti M, Broggini M, Sabapathy K Nucleic Acids Res. 2007;35(6):2093-104. Abstract Tumour-derived p53 mutants are thought to have acquired 'gain-of-function' properties that contribute to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression, leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN. The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently, these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypoacetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable downregulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells, which was found to be due to the induction of apoptosis. Together, the results demonstrate another mechanism through which p53 mutants could promote cellular growth. > 82


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

An Efficient and Safe Herpes Simplex Virus Type 1 Amplicon Vector for Transcriptionally Targeted Therapy of Human Hepatocellular Carcinomas Lam PY, Sia KC, Khong JH, De Geest B, Lim KS, Ho IA, Wang GY, Miao LV, Huynh H, Hui KM Mol Ther. 2007 Jun;15(6):1129-36. Abstract Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy Ang P, Lim IH, Lee TC, Luo JT, Ong DC, Tan PH, Lee AS Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2276-84. Abstract Background and Objective: Genetic testing for germ line mutations in the BRCA1 and BRCA2 genes for some families at high risk for breast and/or ovarian cancer may yield negative results due to unidentified mutations or mutations with unknown clinical significance. We aimed to accurately determine the prevalence of mutations in these genes in an Asian clinic-based population by using a comprehensive testing strategy. Materials and Methods: Ninety-four subjects from 90 families were accrued from risk assessment clinics. In addition to conventional mutational screening of BRCA1 and BRCA2, multiplex ligation-dependent probe amplification for the detection of large genomic rearrangements, evaluation of splice site alterations using transcript analysis and SpliceSiteFinder prediction, and analysis of missense mutations of unknown significance by multiple sequence alignment, PolyPhen analysis, and comparison of Protein Data Bank structures were incorporated into our testing strategy. Results: The prevalence rates for clearly deleterious BRCA1 and BRCA2 mutations were 6.7% (6 of 90) and 8.9% (8 of 90), respectively, or 7.8% (7 of 90) and 11.1% (10 of 90), respectively, by including missense mutations predicted to be deleterious by computational analysis. In contrast to observations from European and American populations, deleterious mutations in BRCA2 (10 families) were more common than for BRCA1 (7 families). Overall, the frequency of mutations was 12.2% (n=11) by conventional screening. However, by including deleterious mutations detected using multiplex ligation-dependent probe amplification (n=1), transcript analysis (n=2), and computational evaluation of missense mutations (n=3), the frequency increased substantially to 18.9%. This suggests that the comprehensive strategy used is effective for identifying deleterious mutations in Asian individuals at high risk for breast and/or ovarian cancer.

> 83


> 84

1.

Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH, Vousden KH, Sabapathy K (2007) p73 supports cellular growth through c-Jun-dependent AP-1 transactivation . Nat Cell Biol 9(6) : 698-705

2.

Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, Cox T, Chong WK, Campbell RH, Bailey CC, Gattamaneni R, Picton S, Thorpe N, Mallucci C, English MW, Punt JA, Walker DA, Ellison DW (2007) Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study . Lancet Oncol 8(8) : 696-705

3.

Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo M, Soo KC (2007) Photodynamic-therapy-activated immune response against distant untreated tumours in recurrent angiosarcoma . Lancet Oncol 8(10) : 950-952

4.

Wong MC, ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A (2007) Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin ESPRIT: a randomised controlled trial . Lancet Neurol 6(2) : 115-24

5.

Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, Sabapathy K (2007) c-Jun promotes cellular survival by suppression of PTEN . Cell Death Differ 14(2) : 218-229

6.

Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG (2007) Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci . Hum Mol Genet 16(11) : 1367-1380

7.

Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, Yap HK (2007) Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats . J Am Soc Nephrol 18(5) : 1476-1485

8.

Iyer NG, Xian J, Chin SF, Bannister AJ, Daigo Y, Aparicio S, Kouzarides T, Caldas C (2007) p300 is required for orderly G1/S transition in human cancer cells . Oncogene 26(1) : 21-29

9.

Furge KA, Tan MH, Dykema K, Kort E, Stadler W, Yao X, Zhou M, Teh BT (2007) Identification of deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomic approach based on gene expression profiling . Oncogene 26(9) : 1346-1350

10.

Leong CT, Ong CK, Tay SK, Huynh H (2007) Silencing expression of UO-44 (CUZD1) using small interfering RNA sensitizes human ovarian cancer cells to cisplatin in vitro . Oncogene 26(6) : 870-880

11.

Ong CK, Leong C, Tan PH, Van T, Huynh H (2007) The role of 5' untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma . Oncogene 26(8) : 1155-1165

12.

Chin SF, Wang Y, Thorne NP, Teschendorff AE, Pinder SE, Vias M, Naderi A, Roberts I, BarbosaMorais NL, Garcia MJ, Iyer NG, Kranjac T, Robertson JF, Aparicio S, TavarĂŠ S, Ellis I, Brenton JD, Caldas C (2007) Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers . Oncogene 26(13) : 1959-1970

13.

Phang BH, Sabapathy K (2007) The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models . Oncogene 26(21) : 2964-2974

14.

Lau WM, Ho TH, Hui KM (2007) p16INK4A-silencing augments DNA damage-induced apoptosis in cervical cancer cells . Oncogene 26(41) : 6050-6060


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

15.

Lim SK, Gopalan G (2007) Antizyme1 mediates AURKAIP1-dependent degradation of AuroraA . Oncogene 26(46) : 6593-6603

16.

De Silva DA, Woon FP, Lee MP, Chen CP, Chang HM, Wong MC (2007) South Asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease . Stroke 38(9) : 2592-2594

17.

Yao X, Qian CN, Zhang ZF, Tan MH, Kort EJ, Yang XJ, Resau JH, Teh BT (2007) Two distinct types of blood vessels in clear cell renal cell carcinoma have contrasting prognostic implications . Clin Cancer Res 13(1) : 161-169

18.

Wang SM, Ooi LL, Hui KM (2007) Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma . Clin Cancer Res 13(21) : 6275-6283

19.

Tan EK, Prakash KM, Fook-Chong S, Yih Y, Chua E, Lum SY, Wong MC, Pavanni R, Zhao Y (2007) DRD3 variant and risk of essential tremor . Neurology 68(10) : 790-791

20.

Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y (2007) Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients . Arch Neurol 64(7) : 1056-1058

21.

Lee MK, Sabapathy K (2007) Phosphorylation at carboxyl-terminal S373 and S375 residues and 14-3-3 binding are not required for mouse p53 function . Neoplasia 9(9) : 690-698

22.

Gough DJ, Sabapathy K, Ko EY, Arthur HA, Schreiber RD, Trapani JA, Clarke CJ, Johnstone RW (2007) A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes . J Biol Chem 282(2) : 938-946

23.

Li YF, Tang RH, Puan KJ, Law SK, Tan SM (2007) The cytosolic protein talin induces an intermediate affinity integrin alphaLbeta2 . J Biol Chem 282(33) : 24310-24319

24.

Kho KW, Shen ZX, Lei Z, Watt F, Soo KC, Olivo M (2007) An Investigation into a Surface Plasmon Related Heating Effect in Surface Enhanced Raman Spectroscopy . Anal Chem 79(23) : 8870-8882

25.

Du HY, Olivo M, Mahendran R, Huang Q, Shen HM, Ong CN, Bay BH (2007) Hypericin photoactivation triggers down-regulation of matrix metalloproteinase-9 expression in welldifferentiated human nasopharyngeal cancer cells . Cell Mol Life Sci 64(7-8) : 979-988

26.

Tan K, Cheang P, Ho IA, Lam PY, Hui KM (2007) Nanosized bioceramic particles could function as efficient gene delivery vehicles with target specificity for the spleen . Gene Ther 14(10) : 828-835

27.

Huynh H, Soo KC, Chow PK, Tran E (2007) Targeted inhibition of the extracellular signalregulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma . Mol Cancer Ther 6(1) : 138-146

28.

Huynh H (2007) Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR22 and CWR-22R prostate cancer xenografts . Mol Cancer Ther 6(8) : 2149-2157

29.

Huynh H, Chow PK, Soo KC (2007) AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma . Mol Cancer Ther 6(9) : 24682476

30.

Huynh H, Teo CC, Soo KC (2007) Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer . Mol Cancer Ther 6(11) : 2959-2966 > 85


> 86

31.

Ha TC, Li H (2007) Meta-analysis of clodronate and breast cancer survival . Br J Cancer 96(12) : 1796-1801

32.

Oh WK, Tay MH, Huang J (2007) Is there a role for platinum chemotherapy in the treatment of patients with hormone-refractory prostate cancer? . Cancer 109(3) : 477-86

33.

Chen W, Salto-Tellez M, Palanisamy N, Ganesan K, Hou Q, Tan LK, Sii LH, Ito K, Tan B, Wu J, Tay A, Tan KC, Ang E, Tan BK, Tan PH, Ito Y, Tan P (2007) Targets of genome copy number reduction in primary breast cancers identified by integrative genomics . Genes Chromosomes Cancer 46(3) : 288-301

34.

Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Liu PQ, Duan W, Chowbay B, Wen JY, Li CG, Zhou SF (2007) Role of P-Glycoprotein in the Intestinal Absorption of Tanshinone IIA, a Major Active Ingredient in the Root of Salvia miltiorrhiza Bunge . Curr Drug Metab 8(4) : 325-340

35.

Yu XY, Lin SG, Chen X, Zhou ZW, Liang J, Duan W, Chowbay B, Wen JY, Chan E, Cao J, Li CG, Zhou SF (2007) Transport of cryptotanshinone, a major active triterpenoid in salvia miltiorrhiza bunge widely used in the treatment of stroke and Alzheimer's disease, across the bloodbrain barrier . Curr Drug Metab 8(4) : 365-378

36.

Wang XD, Li JL, Su QB, Deng XY, Lu Y, Chen J, Zhang JX, Zhao LZ, Zuo Z, Chan E, Chen X, Chowbay B, Xue CC, Huang M, Zhou SF (2007) A pharmacogenetic study of pregnane X receptor (NR1I2) in Han Chinese . Curr Drug Metab 8(8) : 778-786

37.

Capra M, Hewitt M, Radford M, Hayward J, Weston CL, Machin D, Children's Cancer and Leukaemia Group (2007) Long-term outcome in children with Hodgkin's lymphoma: the United Kingdom Children's Cancer Study Group HD82 trial . Eur J Cancer 43(7) : 1171-1179

38.

Ho KY, Cheng J, Wee A, Soo KC (2007) Primary malignant melanoma of the esophagus with multiple esophageal lesions . Nat Clin Pract Gastroenterol Hepatol 4(3) : 171-174

39.

Gao F, Tan SB, Machin D, Wong NS (2007) Confirmation of double-peaked time distribution of mortality for Asian breast cancer patients in a population-based study . Breast Cancer Res 9(2) : R21

40.

Wang GY, Ho IA, Sia KC, Miao L, Hui KM, Lam PY (2007) Engineering An Improved Cell CycleRegulatable Herpes Simplex Virus Type 1 Amplicon Vector with Enhanced Transgene Expression in Proliferating Cells Yet Attenuated Activities in Resting Cells . Hum Gene Ther 18(3) : 222-231

41.

Shim WS, Ho IA, Wong PE (2007) Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis . Mol Cancer Res 5(7) : 655-665

42.

Goh AS, Chung AY, Lo RH, Lau TN, Yu SW, Chng M, Satchithanantham S, Loong SL, Ng DC, Lim BC, Connor S, Chow PK (2007) A novel approach to brachytherapy in hepatocellular carcinoma using a phosphorous(32) ((32)P) brachytherapy delivery device-a first-in-man study . Int J Radiat Oncol Biol Phys 67(3 : 786-792

43.

Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu C, Wong MC (2007) Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis . Int J Radiat Oncol Biol Phys 67(3) : 888-896


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

44.

Whiteman M, Chu SH, Siau JL, Rose P, Sabapathy K, Schantz JT, Cheung NS, Spencer JP, Armstrong JS (2007) The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways . Cell Signal 19(4) : 705-714

45.

Lim SK, Gopalan G (2007) Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway . Biochem J 403(1) : 119-127

46.

Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ (2007) The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence . Hum Genet 120(6) : 857-863

47.

Lian D, Cheah E, Tan PH, Thng CH, Tan SM (2007) Phyllodes tumour with intraductal growth: a rare cause of nipple discharge . Histopathology 50(5) : 666-669

48.

Li XM, Li CC, Yu SS, Chen JT, Sabapathy K, Ruan DY (2007) JNK1 contributes to metabotropic glutamate receptor-dependent long-term depression and short-term synaptic plasticity in the mice area hippocampal CA1 . Eur J Neurosci 25(2) : 391-396

49.

Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam A, Tan EH (2007) Differences between small-cell lung cancer and non-small-cell lung cancer among tobacco smokers . Lung Cancer 56(2) : 161-166

50.

Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Yu XQ, Chowbay B, Wen JY, Duan W, Chan E, Li XT, Cao J, Li CG, Xue CC, Zhou SF (2007) Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra . Pharm Res 24(9) : 16681690

51.

Chin WW, Lau W, Ramaswamy B, Heng PW, Olivo M (2007) Chlorin e6-polyvinylpyrrolidone as a fluorescent marker for fluorescence diagnosis of human bladder cancer implanted on the chick chorioallantoic membrane model . Cancer Lett 245(1-2) : 127-133

52.

Wee HL, Li SC, Xie F, Zhang XH, Luo N, Feeny D, Cheung YB, Machin D, Fong KY, Thumboo J (2007) Validity, feasibility and acceptability of time trade-off and standard gamble assessments in health valuation studies: a study in a multiethnic Asian population in Singapore . Value Health 11 Suppl 1 : S3-S10

53.

Wee HL, Machin D, Loke WC, Li SC, Cheung YB, Luo N, Feeny D, Fong KY, Thumboo J (2007) Assessing differences in utility scores: a comparison of four widely used preference-based instruments . Value Health 10(4) : 256-265

54.

Lal S, Wong ZW, Jada SR, Xiang X, Chen Shu X, Ang PC, Figg WD, Lee EJ, Chowbay B (2007) Novel SLC22A16 polymorphisms and influence on doxorubicin pharmacokinetics in Asian breast cancer patients . Pharmacogenomics 8(6) : 567-575

55.

Yoong JK, Chew LC, Quek R, Lim CH, Zai JQ, Fong KY, Thumboo J (2007) Cardiac lymphoma in primary Sjogren syndrome: a novel case established by targeted imaging and pericardial window . J Thorac Cardiovasc Surg 134(2) : 513-514

56.

Puan KJ, Jin C, Wang H, Sarikonda G, Raker AM, Lee HK, Samuelson MI, M채rker-Hermann E, Pasa-Tolic L, Nieves E, Giner JL, Kuzuyama T, Morita CT (2007) Preferential recognition of a microbial metabolite by human Vgamma2Vdelta2 T cells . Int Immunol 19(5) : 657-673

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> 88

57.

Tan EK, Tong J, Pavanni R, Wong MC, Zhao Y (2007) Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism . Mov Disord 22(13) : 1971-1974

58.

Chia SY, Chua R, Lo YL, Wong MC, Chan LL, Tan EK (2007) Acute ataxia, Graves' disease, and stiff person syndrome . Mov Disord 22(13) : 1969-1971

59.

Tan EK, Zhao Y, Tan L, Lim HQ, Lee J, Yuen Y, Pavanni R, Wong MC, Fook-Chong S, Liu JJ (2007) Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians . Mov Disord 22(12) : 1816-1818

60.

Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, Goh BC, Chowbay B (2007) Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients . Cancer Sci 98(9) : 1461-1467

61.

Thong PS, Olivo M, Kho KW, Zheng W, Mancer K, Harris M, Soo KC (2007) Laser Confocal Endomicroscopy as a Novel Technique for Fluorescence Diagnostic Imaging of the Oral Cavity . J Biomed Opt 12(1) : 014007

62.

Lee AT, Lee CG (2007) Oncogenesis and transforming viruses: the hepatitis B virus and hepatocellularcarcinoma--the etiopathogenic link . Front Biosci 12 : 234-245

63.

Sun YJ, Lee AS, Wong SY, Paton NI (2007) Analysis of the role of Mycobacterium tuberculosis kasA gene mutations in isoniazid resistance . Clin Microbiol Infect 13(8) : 833-835

64.

Wang XD, Li JL, Lu Y, Chen X, Huang M, Chowbay B, Zhou SF (2007) Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatographytandem mass spectrometry: Application to a clinical herb-drug interaction study . J Chromatogr B Analyt Technol Biomed Life Sci 852(1-2) : 534-544

65.

Sun HY, Guan S, Bi HC, Su QB, Huang WL, Chowbay B, Huang M, Chen X, Li CG, Zhou SF (2007) Determination of CH330331, a novel 4-anilinoquinazoline inhibitor of epidermal growth factor receptor tyrosine kinase, in human Caco-2 monolayers by high performance liquid chromatography with ultraviolet detection . J Chromatogr B Analyt Technol Biomed Life Sci 854(1-2) : 320-327

66.

Su QB, He F, Guan S, Lu YJ, Gu LQ, Huang ZS, Chen X, Huang M, Li CG, Chowbay B, Zhou SF (2007) High performance liquid chromatography with ultraviolet detection for the determination of SYUIQ-5, a novel telomerase inhibitor for cancer therapy: Application to an enzyme kinetic study in rat liver microsomes . J Chromatogr B Analyt Technol Biomed Life Sci 854(1-2) : 332337

67.

Yip JL, Aung T, Wong TY, Machin D, Khaw PT, Khaw KT, Seah S, Foster PJ (2007) Socioeconomic status, systolic blood pressure and intraocular pressure: the Tanjong Pagar Study . Br J Ophthalmol 91(1) : 56-61

68.

Yeo W, Boyer M, Chung HC, Ong SY, Lim R, Zee B, Ma B, Lam KC, Mo FK, Ng EK, Ho R, Clarke S, Roh JK, Beale P, Rha SY, Jeung HC, Soo R, Goh BC, Chan AT, Cancer Therapeutics Research Group (CTRG) (2007) Irofulven as first line therapy in recurrent or metastatic gastric cancer: a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG) . Cancer Chemother Pharmacol 59(3) : 295-300

69.

Gao F, Chia KS, Machin D (2007) On the evidence for seasonal variation in the onset of acute lymphoblastic leukemia (ALL) . Leuk Res 31(10) : 1327-1338


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

70.

Bisdas S, Konstantinou GN, Lee PS, Thng CH, Wagenblast J, Baghi M, Koh TS (2007) Dynamic contrast-enhanced CT of head and neck tumors: perfusion measurements using a distributedparameter tracer kinetic model. Initial results and comparison with deconvolution-based analysis . Phys Med Biol 52(20) : 6181-6196

71.

Hui KM (2007) Current approaches in the transcriptional-guided gene therapy of human hepatocellular carcinoma . Curr Opin Mol Ther 9(4) : 378-384

72.

Toh CK, Lim WT (2007) Lung cancer in never-smokers . J Clin Pathol 60(4) : 337-340

73.

Goh BK, Tan YM, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2007) Solid pseudopapillary neoplasms of the pancreas: An updated experience . J Surg Oncol 95(8) : 640-644

74.

CL Saw, M Olivo, T Wohland, CY Fu, KW Kho, KC Soo, PW Heng (2007) Effects of N-Methyl Pyrrolidone on the Uptake of Hypericin in Human Bladder Carcinoma and Co-staining with DAPI Investigated by Confocal Microscopy . Technol Cancer Res Treat 6(5) : 383-394

75.

Goh BK, Tan YM, Chung AY, Chow PK, Cheow PC, Thng CH, Mesenas S, Wong WK, Ooi LL (2007) Pancreatic cysts: a proposed management algorithm based on current evidence . Am J Surg 193(6) : 749-755

76.

Goh BK, Teo MC, Chng SP, Soo KC (2007) Right-sided Bochdalek's hernia in an adult . Am J Surg 194(3) : 390-391

77.

Goh C (2007) The Asia pacific hospice palliative care network: supporting individuals and developing organizations . J Pain Symptom Manage 33(5) : 563-567

78.

De Silva DA, Woon FP, Pin LM, Chen CP, Chang HM, Wong MC (2007) Intracranial large artery disease among OCSP subtypes in ethnic South Asian ischemic stroke patients . J Neurol Sci 260(1-2) : 147-149

79.

Olivo M, Ali SM (2007) Apoptosis signalling mechanisms in human cancer cells induced by Calphostin-PDT . Int J Oncol 30(3) : 537-548

80.

Fu CY, Ng BK, Razul SG, Chin WW, Tan PH, Lau WK, Olivo M (2007) Fluorescence detection of bladder cancer using urine cytology . Int J Oncol 31(3) : 525-530

81.

Quek R, Lim WT, Foo KF, Koo WH, A-Manaf A, Toh HC (2007) Capecitabine and oxaliplatin (XELOX) is safe and effective in patients with advanced gastric cancer . Acta Oncol 46(7) : 1032-1034

82.

Toh CK, Lee P, Chowbay B, Goh JW, Mancer K, Tan PH (2007) An inflammatory response with worsening of pleural effusion on treatment with erlotinib in non-small cell lung cancer . Acta Oncol 46(2) : 256-258

83.

Thia TJ, Lui HF, Ooi LL, Chung AY, Chow PK, Cheow PC, Tan YM, Chow WC (2007) A study into the risk of exacerbation of chronic hepatitis B after liver resection for hepatocellular carcinoma . J Gastrointest Surg 11(5) : 612-618

84.

Thumboo J, Wee HL, Cheung YB, Machin D, Luo N, Feeny D, Fong KY (2007) Computerized administration of health-related quality of life instruments compared to interviewer administration may reduce sample size requirements in clinical research: a pilot randomized controlled trial among rheumatology patients . Clin Exp Rheumatol 25(4) : 577-583

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> 90

85.

Sun YJ, Lee AS, Wong SY, Heersma H, Kremer K, Van Soolingen D, Paton NI (2007) Genotype and Phenotype Relationships and Transmission Analysis of Drug-resistant Tuberculosis in Singapore . Int J Tuberc Lung Dis 11(4) : 436-442

86.

Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2007) Hypericin-mediated photodynamic therapy in combination with Avastin (Bevacizumab) improves tumor response by downregulating angiogenic proteins . Photochem Photobiol Sci 6(12) : 1275-1283

87.

Jada SR, Xiaochen S, Yan LY, Xiaoqiang X, Lal S, Zhou SF, Ooi LL, Chowbay B (2007) Pharmacogenetics of SLCO1B1: haplotypes, htSNPs and hepatic expression in three distinct Asian populations . Eur J Clin Pharmacol 63(6) : 555-563

88.

Lim ST, Gao F, Quek R, Lim LC, Lai LH, Yap SP, Loong SL, Tao M (2007) The relationship of hepatitis B virus infection and non-Hodgkins Lymphoma and its impact on clinical characteristics and prognosis . Eur J Haematol 79(2) : 132-137

89.

Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Duan W, Yu XQ, Wen JY, Chowbay B, Li CG, Sheu FS, Chan E, Zhou SF (2007) Tanshinone IIB, a primary active constituent from Salvia miltiorrhza, exhibits neuro-protective activity in experimentally stroked rats . Neurosci Lett 417(3) : 261265

90.

Sia KC, Wang GY, Ho IA, Khor HY, Miao L, Hui KM, Lam PY (2007) Optimal purification method for Herpes-based viral vectors that confers minimal cytotoxicity for systemic route of vector administration . J Virol Methods 139(2) : 166-174

91.

Liu HB, Gong HQ, Ramalingam N, Jiang Y, Dai CC, Hui KM (2007) Micro Air bubble formation and its control during Polymerase Chain Reaction (PCR) in polydimethylsiloxane (PDMS) microreactors . J Micromech Microeng 17(10) : 2055-2064

92.

Saw CL, Olivo M, Chin WW, Soo KC, Heng PW (2007) Superiority of N-methyl pyrrolidone over albumin with hypericin for fluorescence diagnosis of human bladder cancer cells implanted in the chick chorioallantoic membrane model . J Photochem Photobiol B 86(3) : 207-218

93.

VITATOPS Trial Study Group, Hankey GJ, Algra A, Chen C, Wong MC, Cheung R, Wong L, Divjak I, Ferro J, de Freitas G, Gommans J, Groppa S, Hill M, Spence D, Lees K, Lisheng L, Navarro J, Ranawaka U, Ricci S, Schmidt R, Slivka A, Tan K, Tsiskaridze A, Uddin W, Vanhooren G, Xavier D, Armitage J, Hobbs M, Le M, Sudlow C, Wheatley K, Yi Q, Bulder M, Eikelboom JW, Loh K, Ho WK, Jamrozik K, Klijn K, Koedam E, Langton P, Nijboer E, Tuch P, Pizzi J, Tang M, Antenucci M, Chew Y, Chinnery D, Cockayne C, Chen C, McMullin L, Smith F, Wong MC, Loh K (2007) VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444). . Int J Stroke 2(2) : 144-150

94.

Bisdas S, Baghi M, Wagenblast J, Knecht R, Thng CH, Koh TS, Vogl TJ (2007) Differentiation of benign and malignant parotid tumors using deconvolution-based perfusion CT imaging: feasibility of the method and initial results . Eur J Radiol 64(2) : 258-265

95.

Bhuvaneswari R, Gan YY, Yee KK, Soo KC, Olivo M (2007) Effect of hypericin-mediated photodynamic therapy on the expression of vascular endothelial growth factor in human nasopharyngeal carcinoma . Int J Mol Med 20(4) : 421-428

96.

Shen Y, Wilder-Smith E, Yu E, Ng YK, Ling EA, Spence I, Wong MC (2007) A novel methodology to probe endothelial differential gene expression profile reveals novel genes . Endothelium 14(6) : 303-314


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

97.

Wong CW, Choo SP, Foo KF (2007) The not so innocuous abdominal tap . Palliat Med 21(1) : 62

98.

Lim WT, Zhang WH, Miller CR, Watters JW, Gao F, Viswanathan A, Govindan R, McLeod HL (2007) PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer . Oncol Rep 17(4) : 853-857

99.

Huynh H, Servant N, Chalifour LE (2007) The ubiquinol-cytochrome-c reductase 7.2kD protein of mitochondria complex III is steroid responsive and increased in cardiac hypertrophy and hypertension . Can J Physiol Pharmacol 85(10) : 986-96

100.

Verma S, Wong NS, Trudeau M, Joy A, Mackey J, Dranitsaris G, Clemons M (2007) Survival differences observed in metastatic breast cancer patients treated with capecitabine when compared with vinorelbine after pretreatment with anthracycline and taxane . Am J Clin Oncol 30(3) : 297-302

101.

Tan SB, Machin D (2007) Letter to the Editor: Phase II trial designs in the presence of stratification . Stat Med 25(18) : 3220-3222

102.

Lim ST, Fayad L, Tulpule A, Modiano M, Cabanillas F, Laffranchi B, Allievi C, Bernareggi A, Levine AM (2007) A phase I/II trial of pixantrone (BBR2778), methylprednisolone, cisplatin, and cytosine arabinoside (PSHAP) in relapsed/refractory aggressive non-Hodgkin's lymphoma . Leuk Lymphoma 48(2) : 374-380

103.

Leong SS, Toh CK, Lim WT, Lin X, Tan SB, Poon D, Tay MH, Foo KF, Ho J, Tan EH (2007) A randomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in patients with advanced non-small cell lung cancer who have poor performance status and/or are elderly . J Thorac Oncol 2(3) : 230-236

104.

Lim EH, Zhang SL, Yu K, Nga ME, Ahmed DA, Agasthian T, Wong PS, Chua GC, Wong D, Tan L, Seto KY, Yap WS, Low SP, Khoo KL, Chang A, Ng A, Tan P (2007) An alternative approach to determining therapeutic choices in advanced non-small cell lung carcinoma (NSCLC): maximizing the diagnostic procedure and the use of low-volume lung biopsies . J Thorac Oncol 2(5) : 387-396

105.

Leong SS, Fong KW, Lim WT, Toh CK, Yap SP, Tan EH (2007) Combined modality treatment using a non-platinum-containing regimen and concurrent radiotherapy in the treatment of locally-advanced non-small cell lung cancer . J Thorac Oncol 2(8) : S649

106.

Tan EH, Grodzki T, Schneider CP, Zatloukal P, Reck M, Aitini E, Rolski J (2007) Global Lung Oncology Branch trial 3 (Glob 3): final results of a randomised multinational Phase III study of oral and i.v. vinorelbine (NVB) plus cisplatin (CDDP) versus docetaxel (DTX) plus CDDP as first-line treatment for advanced NSCLC . J Thorac Oncol 2(8) : S451

107.

Lim EH, Tan P (2007) Molecular diagnostics in advanced NSCLC: trying to maximize a nonideal situation . J Thorac Oncol 2(8) : 782

108.

Lim WT, Chuah KL, Agasthian T, Chowbay B, Eng P, Leong SS, Tan EH, Hee SW, Koong HN, Toh CK (2007) Phenotypic differences between sexes and absence of human papillomavirus and Epstein-Barr virus in non-smokers with lung adenocarcinoma in Singapore: P3-011 . J Thorac Oncol 2(8) Suppl4 : S503-S511

109.

Goh BK, Chen JJ, Tan HK, Yong WS, Chan WH (2007) Acute variceal bleed in a patient with idiopathic myelofibrosis successfully treated with endoscopic variceal band ligation . Dig Dis Sci 52(1) : 173-175 > 91


> 92

110.

Chung AY, Chui CH, Tan YM, Kwek BH, Tan HW, Thng CH, Toh HC (2007) Giant Cystic Colorectal Liver Metastasis: An Unusual Presentation . Dig Dis Sci 52(9) : 2333-2335

111.

Choo SP, Venook AP (2007) An alternative therapy for patients with hepatic impairment? . Onkologie 30(10) : 474-475

112.

Lye KW, Wee J, Gao F, Neo PS, Soong YL, Poon CY (2007) The effect of prior radiation therapy for treatment of nasopharyngeal cancer on wound healing following extractions: incidence of complications and risk factors . Int J Oral Maxillofac Surg 36(4) : 315-320

113.

Koo SH, Ong TC, Chong KT, Lee CG, Chew FT, Lee EJ (2007) Multiplexed genotyping of ABC transporter polymorphisms with the Bioplex suspension array . Biol Proced Online 9 : 27-42

114.

Teo HE, Peh WC, Akhilesh M, Tan SB, Ishida T (2007) Congenital osteofibrous dysplasia associated with pseudoarthrosis of the tibia and fibula . Skeletal Radiol 36(Supplement 1) : 7-14

115.

Chew MH, Khoo JB, Chong VF, Tai BC, Soo KC, Lim DT (2007) Significance of tumour volume measurements in tongue cancer: a novel role in staging . ANZ J Surg 77(8) : 632-637

116.

Soon JL, Poopalalingam R, Lim CH, Koong HN, Agasthian T (2007) Peripheral cardiopulmonary bypass-assisted thymoma resection . J Cardiothorac Vasc Anesth 21(6) : 867-869

117.

Toh CK, Hee SW, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Agasthian T, Tan EH (2007) Survival of small-cell lung cancer and its determinants of outcome in Singapore . Ann Acad Med Singapore 36(3) : 181-188

118.

Kang GC, Soo KC, Lim DT (2007) Extracranial non-vestibular head and neck schwannomas: a ten-year experience . Ann Acad Med Singapore 36(4) : 233-238

119.

See SJ, Ty A, Wong MC (2007) Salvage chemotherapy in progressive high-grade astrocytoma . Ann Acad Med Singapore 36(5) : 343-346

120.

Wee HL, Loke WC, Li SC, Fong KY, Cheung YB, Machin D, Luo N, Thumboo J (2007) Cross-Cultural Adaptation and Validation of Singapore Malay and Tamil Versions of the EQ5D . Ann Acad Med Singapore 36(6) : 403-406

121.

Low JS, Koh WY, Yap SP, Fong KW (2007) Radical Radiotherapy in Stage I Non-small Cell Lung Cancer (NSCLC) - Singapore National Cancer Centre Experience . Ann Acad Med Singapore 36(9) : 778-783

122.

Ngo LS, Yeo A, Wong AS, Tay MH (2007) Efficacy of Low-dose Ketoconazole in Hormone Refractory Prostate Cancer Patients at the National Cancer Centre and The Cancer Institute, Singapore . Ann Acad Med Singapore 36(10) : 811-814

123.

Wijaya R, Yong WS, Yeo AW, See DT (2007) Managing breast cancer diagnosed in first trimester pregnancy: a case report . Ann Acad Med Singapore 36(12) : 1024-1027

124.

De Silva DA, Ong SH, Elumbra D, Wong MC, Chen CL, Chang HM (2007) Timing of hospital presentation after acute cerebral infarction and patients' acceptance of intravenous thrombolysis . Ann Acad Med Singapore 36(4) : 244-246

125.

Chandran NS, Greaves M, Gao F, Lim L, Cheng BC (2007) Psoriasis and the eye: prevalence of eye disease in Singaporean Asian patients with psoriasis . J Dermatol 34(12) : 805-810


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

126.

Goh BK, Yeo AW, Koong HN, Ooi LL, Wong WK (2007) Laparotomy for Acute Complications of Gastrointestinal Metastases from Lung Cancer: Is it a Worthwhile or Futile Effort? . Surg Today 37(5) : 370-374

127.

Zhou JY, Chong VF, Khoo JB, Chan KL, Huang J (2007) The relationship between nasopharyngeal carcinoma tumor volume and TNM T-classification: a quantitative analysis . Eur Arch Otorhinolaryngol 264(2) : 169-174

128.

Yeow VK, Lee ST, Cheng JJ, Koh A, Wong HB, Machin D (2007) Randomised clinical trials in plastic surgery: Survey of output and quality of reporting . J Plast Reconstr Aesthet Surg 60(8) : 965-966

129.

Kah JC, Kho KW, Lee CG, Sheppard CJ, Shen ZX, Soo KC, Olivo M (2007) Early diagnosis of oral cancer based on the surface plasmon resonance of gold nanoparticles . Int J Nanomedicine 2(4) : 785-798

130.

Machin D, Tan SB (2007) Biometrical aspects of drug development . Ernst Schering Res Found Workshop (59) : 195-207

131.

Machin D, Tan SB (2007) Biometrical aspects of drug development . Appropriate Dose Selection: How to optimize clinical drug development Chapt 15 : 195-208

132.

Wang Z, Chong SS, Lee CG (2007) Characterization of Single Nucleotide Polymorphisms in 13 Members of the ABC Drug Transporter Genes in Three Different Populations . The Open Pharmacol J 1 : 1-12

133.

Chin WW, Heng PW, Olivo M (2007) Chlorin e6 - polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts . BMC Pharmacol 7(1) : 15

134.

Ha TC (2007) Genetic Epidemiology of Cancer . SGH Proceedings 16(3) : 148-151

135.

Xu Y, Singh J, Teo HS, Ramakrishna K, Premchandran CS, Chen WS, Kuan CT, Chen NK, Olivo M, Sheppard CJR (2007) MEMS-based non-rotatory circumferential scanning optical probe for endoscopic optical coherence tomography . Proc SPIE 6627 : 662715

136.

Olivo M (2007) New endoscopic technology to detect cancer. The latest confocal endomicroscopy allows early cancer diagnosis at high resolution . Innovations 7(1) : 27-28

137.

Huynh H, Tai ES, Gillies PJ (2007) Nutrigenomics-Opportunities in Asia . Forum Nutr 60 : 146157

138.

Chin WW, Ramaswamy B, Thong PS, Heng PW, Gan YY, Olivo M, Soo KC (2007) Preclinical and Pilot Clinical Cancer Studies Using Fluorescence-guided Photodynamic Therapy with Chlorin e6-polyvinylpyrrolidone and Hypericin . SGH Proceedings 16(3) : 118-126

139.

Singh J, Chan CH, Teo HS, Chen NK, Premachandran CS, Sheppard C, Olivo M (2007) Optical coherent tomography (OCT) bio-imaging using 3D scanning micromirror . Proc SPIE 6432 : 12.702279

140.

Mashfiqul MA, Tan YM, Thng CH, Cheow PC, Chung AY, Chow PK, Ooi LL (2007) Pedunculated HCC or adrenal metastasis: a diagnostic conundrum . Singapore Med J 48(2) : e50-2

141.

Kho KW, Kah JC, Lee CG, Sheppard CJ, Shen ZX, Soo KC, Olivo M (2007) Applications of gold nanoparticles in the early detection of oral cancer . J Mech Med Biol 7(1) : 19 - 35 > 93


> 94

142.

Thong PS, Kho KW, Zheng W, Harris M, Soo KC, Olivo M (2007) Development of a Laser Confocal Endomicroscope for In Vivo Fluorescence Imaging . J Mech Med Biol 7(1) : 11-18

143.

Sreedharan S, Tan YM, Tan SG, Soo KC, Wong WK (2007) Clinical spectrum and surgical management of acute mesenteric ischaemia in Singapore . Singapore Med J 48(4) : 319-323

144.

Tan HH, Ooi LL, Tan D, Tan CK (2007) Recurrent abdominal pain in a woman with a wandering spleen . Singapore Med J 48(4) : e122-124

145.

Goh BK, Chung AY, Ng DC, Selvarajan S, Soo KC (2007) Positron emission tomography with 2-deoxy-2-[18f] fluoro-D-glucose in the detection of malignancy in intraductal papillary mucinous neoplasms of the pancreas . J Pancreas 8(3) : 350-354

146.

Zhou SF, Chowbay B (2007) Clinical Significance of Thiopurine S-Methyltransferase Gene Polymorphisms . Curr Pharmacogenomics 5(2) : 103-115

147.

Mashfiqul MA, Tan YM, Chintana CW (2007) Endometriosis of the inguinal canal mimicking a hernia . Singapore Med J 48(6) : e157-159

148.

Zhou SF, Chowbay B, Xue CC (2007) Pharmacogenetics of oxazaphosphorines and the clinical applications . Curr Pharmacogenomics 5(2) : 143-156

149.

Sreedharan S, Pang CE, Chan GS, Soo KC, Lim DT (2007) Follicular thyroid carcinoma presenting as axial skeletal metastases . Singapore Med J 48(7) : 640-644

150.

Soo KC (2007) Voice Conservation Surgery For Laryngeal And Hypopharyngeal Cancer . Singapore Med J 48(7) : 701

151.

Choo SP, Lal S, Chowbay B (2007) Pharmacogenetics and ethnicity: An Asian perspective . Pharmacogenomics in Admixed Populations. URL: http://www.landesbioscience.com/books/iu/id/959 9 : 133-152

152.

Huynh H (2007) Dietary quercetin inhibits proliferation of lung carcinoma cells . Forum Nutr 60 : 146-157

153.

Ong JC, Chow PK, Chan WH, Chung AY, Thng CH, Wong WK (2007) Hepatocellular carcinoma masquerading as a bleeding gastric ulcer: A case report and a review of the surgical management . World J Gastroenterol 13(33) : 4523-4525

154.

Chang AY, Lopes G, Koo WH, Lim R, Fong FK, Wong JS (2007) Phase II Trial of 5Fluorouracil/Leucovorin/Gemcitabine/Cisplatin as Second-Line Treatment in Patients with Metastatic or Recurrent Colorectal Carcinoma: A Cancer Therapeutics Research Group Study . Clin Colorectal Cancer 6(9) : 646-651

155.

Khor TH, Tuan JK, Hee SW, Tham IW (2007) Radical radiotherapy with high-dose rate (HDR) brachytherapy for uterine cervix cancer - long term results . Australas Radiol 51(6)-7 : 570577

156.

Ho SY, Choo SP (2007) Oncological Emergencies: An Overview and Approach . SGH Proceedings 16(2) : 63-71


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

157.

De Silva DA, Wong MC, Lee MP, Chen CL, Chang HM (2007) Amphetamine-associated ischemic stroke: clinical presentation and proposed pathogenesis . J Stroke Cerebrovasc Dis 16(4) : 185-186

158.

De Silva DA, Woon FP, Xie XY, Li Hsian Chen C, Chang HM, Wong MC (2007) Metabolic syndrome among ethnic South Asian patients with ischemic stroke and comparison with ethnic Chinese patients: the Singapore General Hospital experience . J Stroke Cerebrovasc Dis 16(3) : 119121

> 95


Highlighted Publications for 2008:

Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated ELGN2mediated oxygen-sensing response Koeman JM, Russell RC, Tan MH, Petillo D, Westphal M, Koelzer K, Metcalf JL, Zhang Z, Matsuda D, Dykema KJ, Houseman HL, Kort EJ, Furge LL, Kahnoski RJ, Richard S, Vieillefond A, Swiatek PJ, Teh BT, Ohh M, Furge KA PLoS Genet. 2008 Sep 5;4(9):e1000176. Abstract Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2 [corrected] a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 [corrected] in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer Hou Q, Wu YH, Grabsch H, Zhu Y, Leong SH, Ganesan K, Cross D, Tan LK, Tao J, Gopalakrishnan V, Tang BL, Kon OL, Tan P Cancer Res. 2008 Jun 15;68(12):4623-30. Abstract Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution arraybased comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining high-resolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration.

> 96


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells Zhao Y, Hamza MS, Leong HS, Lim CB, Pan YF, Cheung E, Soo KC, Iyer NG Oncogene. 2008 Jan 3;27(1):1-8. Abstract Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity. Clinical validation of a customized multiple signature microarray for breast cancer Tan BK, Tan LK, Yu K, Tan PH, Lee M, Sii LS, Wong CY, Ho GH, Yeo AW, Chow PK, Koong HN, Yong WS, Lim DT, Ooi LL, Soo KC, Tan P Clin Cancer Res. 2008 Jan 15;14(2):461-9. Abstract Purpose: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice. Experimental Design We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and "basaloid"], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer. Results: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio > or =2.2; P < 0.001), which further improved to 89% when the ratio cutoff was raised to > or =5. A proportion of lowlevel FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019). Conclusion: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice.

> 97


PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients Sandanaraj E, Lal S, Selvarajan V, Ooi LL, Wong ZW, Wong NS, Ang PC, Lee EJ, Chowbay B Clin Cancer Res. 2008 Nov 1;14(21):7116-26. Abstract Purpose: To characterize pregnane X receptor (PXR) polymorphic variants in healthy Asian populations [Chinese, Malay and Indian (n=100 each)], and to investigate the association between PXR haplotypes and hepatic mRNA expression of PXR and its downstream target genes, CYP3A4 and ABCB1, as well as their influence on the clearance of doxorubicin in Asian breast cancer patients. Experimental Design: PXR genotyping was done by direct DNA sequencing, and PXR haplotypes and haplotype clusters were derived by expectation-maximization algorithm. Genotype-phenotype correlations were done using Mann-Whitney U test and Kruskal-Wallis test. Results: Significant interethnic variations were observed in PXR pharmacogenetics among the three Asian ethnic groups. The expression of PXR mRNA in liver tissues harboring the PXR*1B haplotype clusters was 4-fold lower compared with the non-PXR*1B (*1A + *1C) haplotype clusters [PXR*1B versus PXR*1A; P=0.015; PXR*1B versus PXR*1C; P=0.023]. PXR*1B-bearing liver tissues were associated with significantly lower expression of CYP3A4 (PXR*1B versus non-PXR*1B, P=0.030) and ABCB1 (PXR*1B versus nonPXR*1B, P=0.060) compared with non-PXR*1B-bearing liver tissues. Doxorubicin clearance in breast cancer patients harboring the PXR*1B haplotypes was significantly lower compared with patients carrying the non-PXR*1B haplotypes [PXR*1B versus non-PXR*1B, CL/BSA (L h(-1) m(-2)): 20.84 (range, 8.6829.24) versus 24.85 (range, 13.80-55.66), P=0.022]. Conclusions: This study showed that PXR*1B was associated with reduced hepatic mRNA expression of PXR and its downstream targets, CYP3A4 and ABCB1. Genotype-phenotype correlates in breast cancer patients showed PXR*1B to be significantly associated with lower doxorubicin clearance, suggesting that PXR haplotype constitution could be important in influencing interindividual and interethnic variations in disposition of its putative drug substrates.

> 98


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

1.

Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlรถ B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC, PRoFESS Study Group (2008) Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke . New Eng J Med 359(12) : 1238-1251

2.

Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlรถ'f6f B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC, PRoFESS Study Group (2008) Telmisartan to prevent recurrent stroke and cardiovascular events. . New Eng J Med 359(12) : 1225-1237

3.

Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer . Science 322(5908) : 1695-1699

4.

Lee AS, Ang P (2008) CHEK2*1100delC screening of Asian women with a family history of breast cancer is unwarranted . J Clin Oncol 26(14) : 2419-2420

5.

Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlรถ B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC (Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group) (2008) Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study . Lancet Neurol 7(10) : 875-84

6.

Soo KC (2008) Role of comprehensive cancer centres during economic and disease transition: National Cancer Centre, Singapore--a case study . Lancet Oncol 9(8) : 796-802

7.

Toh CK (2008) Refining the bipartite model of lung cancer . Lancet Oncol 9(10) : 918-919

8.

Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, van Lohuizen M (2008) Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium . Curr Biol 18(14) : 1094-1099

9.

Sim SH, Yu Y, Lin CH, Karuturi RK, Wuthiekanun V, Tuanyok A, Chua HH, Ong C, Paramalingam SS, Tan G, Tang L, Lau G, Ooi EE, Woods D, Feil E, Peacock SJ, Tan P (2008) The core and accessory genomes of Burkholderia pseudomallei: implications for human melioidosis . PLoS Pathog 4(10) : e1000178

10.

Yu K, Ganesan K, Tan LK, Laban M, Wu J, Zhao XD, Li H, Leung CH, Zhu Y, Wei CL, Hooi SC, Miller L, Tan P (2008) A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers . PLoS Genet 4(7) : e1000129

11.

Sabapathy K, Nam SY (2008) Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function . Cell Death Differ 15(9) : 1364-1374

> 99


12.

Ganesan K, Ivanova T, Wu Y, Rajasegaran V, Wu J, Lee MH, Yu K, Rha SY, Chung HC, Ylstra B, Meijer G, Kon OL, Grabsch H, Tan P (2008) Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel beta-catenin/TCF target gene . Cancer Res 68(11) : 4277-4286

13.

Kort EJ, Farber L, Tretiakova M, Petillo D, Furge KA, Yang XJ, Cornelius A, Teh BT (2008) The E2F3-Oncomir-1 axis is activated in Wilms' tumor . Cancer Res 68(11) : 4034-4038

14.

Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS, Resau JH, Teh BT (2008) Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo . Cancer Res 68(1) : 81-88

15.

Lin CH, Bourque G, Tan P (2008) A comparative synteny map of burkholderia species links largescale genome rearrangements to fine-scale nucleotide variation in prokaryotes . Mol Biol Evol 25(3) : 549-558 Liu BH, Goh CH, Ooi LL, Hui KM (2008) Identification of unique and common low abundance tumour-specific transcripts by suppression subtractive hybridization and oligonucleotide probe array analysis . Oncogene 27(29) : 4128-4136

16.

> 100

17.

Huynh H, Chow PK, Palanisamy N, Salto-Tellez M, Goh BC, Lee CK, Somani A, Lee HS, Kalpana R, Yu K, Tan PH, Wu J, Soong R, Lee MH, Hor H, Soo KC, Toh HC, Tan P (2008) Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma . J Hepatol 49(1) : 52-60

18.

Toh WH, Logette E, Corcos L, Sabapathy K (2008) TAp73beta and DNp73beta activate the expression of the pro-survival caspase-2S . Nucleic Acids Res 36(13) : 4498-4509

19.

De Silva DA, Wong TY, Chang HM, Ng BF, Tikellis G, Saw SM, Woon FP, Chen CP, Wong MC (2008) Is routine retinal examination useful in patients with acute ischemic stroke? . Stroke 39(4) : 1352-1354

20.

De Silva DA, Woon FP, Chen CPLH, Chang HM, Wong MC (2008) Response to Letter by Sheik . Stroke 39(1): : e2

21.

Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung AY, Chow PK, Pollock P, Byron S, Tran E (2008) Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma . Clin Cancer Res 14(19) : 6146-6153

22.

Peacock SJ, Schweizer HP, Dance DA, Smith TL, Gee JE, Wuthiekanun V, DeShazer D, Steinmetz I, Tan P, Currie BJ (2008) Management of accidental laboratory exposure to Burkholderia pseudomallei and B. mallei . Emerg Infect Dis 14(7) : e2

23.

Lee MK, Sabapathy K (2008) The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo . J Cell Science 121(Pt 11) : 1899-1906

24.

Sarikonda G, Wang H, Puan KJ, Liu XH, Lee HK, Song Y, Distefano MD, Oldfield E, Prestwich GD, Morita CT (2008) Photoaffinity antigens for human gammadelta T cells . J Immunol 181(11) : 7738-7750

25.

Koh TS, Thng CH, Lee PS, Hartono S, Rumpel H, Goh BC, Bisdas S (2008) Hepatic metastases: in vivo assessment of perfusion parameters at dynamic contrast-enhanced MR imaging with dual-input two-compartment tracer kinetics model . Radiology 249(1) : 307-320


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

26.

Tan KC (2008) The right posterior hepatic notch sign . Radiology 248(1) : 317-318

27.

Wang P, Bowl MR, Bender S, Peng J, Farber L, Chen J, Ali A, Zhang Z, Alberts AS, Thakker RV, Shilatifard A, Williams BO, Teh BT (2008) Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice . Mol Cell Biol 28(9) : 2930-2940

28.

Bisdas S, Donnerstag F, Berding G, Vogl TJ, Thng CH, Koh TS (2008) Computed tomography assessment of cerebral perfusion using a distributed parameter tracer kinetics model: validation with H(2)((15))O positron emission tomography measurements and initial clinical experience in patients with acute stroke . J Cereb Blood Flow Metab 28(2) : 402-411

29.

Meng W, Zhang H, Guo T, Pandey C, Zhu Y, Kon OL, Sze SK (2008) One-Step Procedure for Peptide Extraction from In-Gel Digestion Sample for Mass Spectrometric Analysis . Anal Chem 80(24) : 9379-9851

30.

Ou K, Yu K, Kesuma D, Hooi M, Huang N, Chen W, Lee SY, Goh XP, Tan LK, Liu J, Soon SY, Bin Abdul Rashid S, Putti TC, Jikuya H, Ichikawa T, Nishimura O, Salto-Tellez M, Tan P (2008) Novel breast cancer biomarkers identified by integrative proteomic and gene expression mapping . J Proteome Res 7(4) : 1518-1528

31.

Guo T, Gan CS, Zhang H, Zhu Y, Kon OL, Sze SK (2008) Hybridization of Pulsed-Q Dissociation and Collision-Activated Dissociation in Linear Ion Trap Mass Spectrometer for iTRAQ Quantitation . J Proteome Res 7(11) : 4831-4840

32.

Teo CR, Wang W, Yang Law H, Lee CG, Chong SS (2008) Single-step scalable-throughput molecular screening for Huntington disease . Clin Chem 54(6) : 964-972

33.

Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG (2008) Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 upregulation and apoptosis inhibitor-5 as a microRNA-224-specific target . J Biol Chem 283(19) : 13205-13215

34.

Sandanaraj E, Jada SR, Shu X, Lim R, Lee SC, Zhou Q, Zhou S, Goh BC, Chowbay B (2008) Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients . Pharmacogenomics J 8(3) : 174-185

35.

Bhuvaneswari R, Gan YY, Lucky SS, Chin WW, Ali SM, Soo KC, Olivo M (2008) Molecular profiling of angiogenesis in hypericin mediated photodynamic therapy . Mol Cancer 7 : 56

36.

Leong SS, Wee J, Rajan S, Toh CK, Lim WT, Hee SW, Tay MH, Poon D, Tan EH (2008) Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma . Cancer 113(6) : 1332-1337

37.

Lee HH, Zhu Y, Govindasamy KM, Gopalan G (2008) Downregulation of aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells . Endocr Relat Cancer 15(3) : 765-775

38.

Pietersen AM, Horlings HM, Hauptmann M, Langerød A, Ajouaou A, Cornelissen-Steijger P, Wessels LF, Jonkers J, van de Vijver MJ, van Lohuizen M (2008) EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer . Breast Cancer Res 10(6) : R109

> 101


> 102

39.

Ryan G, Martinelli G, Kuper-Hommel M, Tsang R, Pruneri G, Yuen K, Roos D, Lennard A, Devizzi L, Crabb S, Hossfeld D, Pratt G, Dell'olio M, Choo SP, Bociek RG, Radford J, Lade S, Gianni AM, Zucca E, Cavalli F, Seymour JF (2008) Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group . Ann Oncol 19(2) : 233-241

40.

Boyle P, Anderson BO, Andersson LC, Ariyaratne Y, Auleley GR, Barbacid M, Bartelink H, Baselga J, Behbehani K, Belardelli F, Berns A, Bishop J, Brawley O, Burns H, Clanton M, Cox B, Currow D, Dangou JM, de Valeriola D, Dinshaw K, Eggermont A, Fitzpatrick J, Forstmane M, Garaci E, Gavin AT, Kakizoe T, Kasler M, Keita N, Kerr D, Khayat D, Khleif S, Khuhaprema T, Knezevic T, Kubinova R, Mallath M, Martin-Moreno J, McCance D, McVie JG, Merriman A, Ngoma T, Nowacki M, Orgelbrand J, Park JG, Pierotti M, Ashton LP, Puska P, Escobar CV, Rajan B, Rajkumar T, Ringborg U, Robertson C, Rodger A, Roovali L, Santini LA, Sarhan M, Seffrin J, Semiglazov V, Shrestha BM, Soo KC, Stamenic V, Tamblyn C, Thomas R, Tuncer M, Tursz T, Vaitkiene R, Vallejos C, Veronesi U, Wojtyla A, Yach D, Yoo KY, Zatonski W, Zaridze D, Zeng YX, Zhao P, Zheng T (2008) Need for global action for cancer control . Ann Oncol 19(9) : 1519-1521

41.

Lum SS, Chua HW, Li H, Li WF, Rao N, Wei J, Shao Z, Sabapathy K (2008) MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset-age of sporadic breast cancers in the Chinese population . Carcinogenesis 29(4) : 754-761

42.

Tan HK, Saulnier P, Auperin A, Lacroix L, Casiraghi O, Janot F, Fouret P, Temam S (2008) Quantitative methylation analyses of resection margins predict local recurrences and diseasespecific deaths in patients with head and neck squamous cell carcinomas . Br J Cancer 99(2) : 357-363

43.

Morris MR, Gentle D, Abdulrahman M, Clarke N, Brown M, Kishida T, Yao M, Teh BT, Latif F, Maher ER (2008) Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma . Br J Cancer 98(2) : 496-501

44.

Tan WM, Paterson MC, Koo GC, Li HH, Price A, Loong SL (2008) Increased but error-prone nonhomologous end joining in immortalized lymphoblastoid cell extracts from adult cancer patients with late radionecrosis . Int J Radiat Oncol Biol Phys 72(1) : 178-185

45.

Nam SY, Lee MK, Sabapathy K (2008) The tumour-suppressor p53 is not required for pancreatic Ă&#x; cell death during diabetes and upon irradiation . J Physiol-London 586(2) : 407-417

46.

Phang BH, Linn YC, Li H, Sabapathy K (2008) MDM2 SNP309 G allele decreases risk but does not affect onset age or survival of Chinese leukaemia patients . Eur J Cancer 44(5) : 760766

47.

Goh BK, Tan YM, Chung AY, Cheow PC, Ong HS, Chan WH, Chow PK, Soo KC, Wong WK, Ooi LL (2008) Critical appraisal of 232 consecutive distal pancreatectomies with emphasis on risk factors, outcome, and management of the postoperative pancreatic fistula: a 21-year experience at a single institution . Arch Surg 143(10) : 956-965

48.

Lee TC, Lee AS, Li KB (2008) Incorporating the amino acid properties to predict the significance of missense mutations . Amino Acids 35(3) : 615-626

49.

Tan SY, Ye H, Liu H, Lim KH, Toh HC, Ng CF, Chung AY, Wotherspoon AC, Du MQ (2008) t(11;18)(q21;q21)-positive transformed MALT lymphoma . Histopathology 52(6) : 777-780

50.

Phonthammachai N, Kah JC, Jun G, Sheppard CJ, Olivo M, Mhaisalkar SG, White TJ (2008) Synthesis of contiguous silica-gold core-shell structures: critical parameters and processes . Langmuir 24(9) : 5109-5112


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

51.

Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, Shah RB, Yang Y, Chuang ST, Lin F, Tretiakova MM, Kort EJ, Teh BT (2008) Tubulocystic carcinoma of the kidney: clinicopathologic and molecular characterization . Am J Surg Pathol 32(2) : 177-187

52.

Camparo P, Vasiliu V, Molinie V, Couturier J, Dykema KJ, Petillo D, Furge KA, Comperat EM, Lae M, Bouvier R, Boccon-Gibod L, Denoux Y, Ferlicot S, Forest E, Fromont G, Hintzy MC, Laghouati M, Sibony M, Tucker ML, Weber N, Teh BT, Vieillefond A (2008) Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature . Am J Surg Pathol 32(5) : 656-670

53.

Chuang ST, Patton KT, Schafernak KT, Papavero V, Lin F, Baxter RC, Teh BT, Yang XJ (2008) Over expression of insulin-like growth factor binding protein 3 in clear cell renal cell carcinoma . J Urology 179(2) : 445-449

54.

Tan KD, Zhu Y, Tan HK, Rajasegaran V, Aggarwal A, Wu J, Wu HY, Hwang J, Lim DT, Soo KC, Tan P (2008) Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma . Genes Chromosomes Cancer 47(4) : 353362

55.

Goh BK, Tan YM, Thng CH, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2008) How useful are clinical, biochemical, and cross-sectional imaging features in predicting potentially malignant or malignant cystic lesions of the pancreas? Results from a single institution experience with 220 surgically treated patients . J Am Coll Surg 206(1) : 17-27

56.

Bisdas S, Medov L, Baghi M, Konstantinou GN, Wagenblast J, Thng CH, Vogl TJ, Koh TS (2008) A comparison of tumour perfusion assessed by deconvolution-based analysis of dynamic contrast-enhanced CT and MR imaging in patients with squamous cell carcinoma of the upper aerodigestive tract . 18(4) : 843-850

57.

Bisdas S, Rumboldt Z, Surlan K, Koh TS, Deveikis J, Spampinato MV (2008) Perfusion CT measurements in healthy cervical spinal cord: feasibility and repeatability of the study as well as interchangeability of the perfusion estimates using two commercially available software packages . Eur Radiol 18(10) : 2321-2328

58.

Kah JC, Wan RC, Wong KY, Mhaisalkar S, Sheppard CJ, Olivo M (2008) Combinatorial treatment of photothermal therapy using gold nanoshells with conventional photodynamic therapy to improve treatment efficacy: an in vitro study . Lasers Surg Med 40(8) : 584-589

59.

Tan DS, Eng PC, Lim ST, Tao M (2008) Primary tracheal lymphoma causing respiratory failure . J Thorac Oncol 3(8) : 929-930

60.

Matsuda D, Khoo SK, Massie A, Iwamura M, Chen J, Petillo D, Wondergem B, Avallone M, Kloostra SJ, Tan MH, Koeman J, Zhang Z, Kahnoski RJ; French Kidney Cancer Study Group, Baba S, Teh BT (2008) Identification of copy number alterations and its association with pathological features in clear cell and papillary RCC . Cancer Lett 272(2) : 260-267

61.

Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, Chowbay B (2008) CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. . Cancer Sci 99(10) : 2045-2054

62.

Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ, Chowbay B (2008) Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients . Cancer Sci 99(4) : 816-823

> 103


> 104

63.

Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT, Zee B, Mok T (2008) A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells . Invest New Drugs 26(2) : 169-173

64.

Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, Gomez RS, Tavares GC, Eng C, De Marco L (2008) Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations . Surgery 143(5) : 630-640

65.

Chin WW, Heng PW, Thong PS, Bhuvaneswari R, Hirt W, Kuenzel S, Soo KC, Olivo M (2008) Improved formulation of photosensitizer chlorin e6 polyvinylpyrrolidone for fluorescence diagnostic imaging and photodynamic therapy of human cancer . Eur J Pharm Biopharm 69(3) : 1083-1093

66.

Wong WY, Wong JS (2008) Uptake of Tc-99m Methylene Diphosphonate in Peritoneal Metastases From Breast Cancer . Clin Nucl Med 33(3) : 218-219

67.

Kolomeichuk SN, Terrano DT, Lyle CS, Sabapathy K, Chambers TC (2008) Distinct signaling pathways of microtubule inhibitors - vinblastine and Taxol induce JNK-dependent cell death but through AP-1-dependent and AP-1-independent mechanisms, respectively . FEBS J 275(8) : 1889-1899

68.

Lal S, Sandanaraj E, Jada SR, Kong MC, Lee LH, Goh BC, Lee SC, Chowbay B (2008) Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients. . Br J Clin Pharmacol 65(2) : 260-264

69.

Cao S, Ho GH, Lin VC (2008) Tetratricopeptide repeat domain 9A is an interacting protein for tropomyosin Tm5NM-1 . BMC Cancer 8 : 231

70.

Yap KY, Chui WK, Chan A (2008) Drug interactions between chemotherapeutic regimens and antiepileptics . Clin Ther 30(8) : 1385-1407

71.

Teo FS, Hsu AA, Agasthian T (2008) Recurrent foreign body granuloma with airway obstruction: is there a role for steroids? . J Thorac Cardiovasc Surg 136(1) : 224-225

72.

Wee HL, Cheung YB, Loke WC, Tan CB, Chow MH, Li SC, Fong KY, Feeny D, Machin D, Luo N, Thumboo J (2008) The association of body mass index with health-related quality of life: an exploratory study in a multiethnic Asian population . Value Health 11 Suppl 1 : S105-S114

73.

Ho IA, Chan KY, Miao L, Shim WS, Guo CM, Cheang P, Hui KM, Lam PY (2008) HSV-1 amplicon viral vector-mediated gene transfer to human bone marrow-derived mesenchymal stem cells . Cancer Gene Ther 15(9) : 553-562

74.

Kah JC, Lau WK, Tan PH, Sheppard CJ, Olivo M (2008) Endoscopic image analysis of photosensitizer fluorescence as a promising noninvasive approach for pathological grading of bladder cancer in situ . J Biomed Opt 13(5) : 054022

75.

Kho KW, Qing KZ, Shen ZX, Ahmad IB, Lim SS, Mhaisalkar S, White TJ, Watt F, Soo KC, Olivo M (2008) Polymer-based microfluidics with surface-enhanced Raman-spectroscopy-active periodic metal nanostructures for biofluid analysis . J Biomed Opt 13(5) : 054026

76.

Tsao CC, Teh BT, Jonasch E, Shreiber-Agus N, Efstathiou E, Hoang A, Czerniak B, Logothetis C, Corn PG (2008) Inhibition of Mxi1 suppresses HIF-2alpha-dependent renal cancer tumorigenesis . Cancer Biol Ther 7(10) : 1619-1627


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

77.

Lim WT, Baggstrom MQ, Read W, Fracasso PM, Govindan R (2008) A Phase I trial of weekly docetaxel and topotecan for solid tumors . Acta Oncol 47(2) : 311-315

78.

Ngeow JY, Prakash KM, Chowbay B, Quek ST, Choo SP (2008) Capecitabine-induced oromandibular dystonia: A case report and literature review . Acta Oncol 447(6) : 1161-1165

79.

De Silva DA, Woon FP, Gan HY, Cameron J, Kingwell B, Koh TH, Chen C, Chang HM, Wong MC (2008) Arterial stiffness, metabolic syndrome and inflammation amongst Asian ischaemic stroke patients . Eur J Neurol 15(8) : 872-875

80.

De Silva D, Woon FP, Chen C, Chang HM, Kingwell B, Cameron J, Wong MC (2008) Profile and associations of central pulse wave velocity and central pulse pressure among ischemic stroke patients . Eur J Neurol 15(2) : 196-198

81.

Moe KT, Woon FP, De Silva DA, Wong P, Koh TH, Kingwell B, Chin-Dusting J, Wong MC (2008) Association of acute ischemic stroke with the MTHFR C677T polymorphism but not with NOS3 gene polymorphisms in a Singapore population . Eur J Neurol 15(12) : 1309-1314

82.

Bisdas S, Baghi M, Wagenblast J, Vogl TJ, Thng CH, Koh TS (2008) Gadolinium-enhanced echo-planar T2-weighted MRI of tumors in the extracranial head and neck: Feasibility study and preliminary results using a distributed-parameter tracer kinetic analysis . J Magn Reson Imaging 27(5) : 963-969

83.

Koh TS, Thng CH, Ho JT, Tan PH, Rumpel H, Khoo JB (2008) Independent component analysis of dynamic contrast-enhanced magnetic resonance images of breast carcinoma: A feasibility study . J Magn Reson Imaging 28(1) : 271-277

84.

Chew MH, Chan G, Siddiqui MM, Tai BC, Sivanandan R, Soo KC, Lim DT (2008) Risk-stratified Management of Well-differentiated Thyroid Cancers: A Review of Experience from a Single Institution, 1990-2003 . World J Surg 32(3) : 386-394

85.

Tan EK, Sie L, Loong SL (2008) Growth rate of patient-derived lymphoblastoid cells with LRRK2 mutations . Mol Genet Metab 95(1-2) : 113

86.

Tan CY, Ho JF, Yap SC, Loganath A, Chan YH, Jeganathan R, Lee CG, Chong SS (2008) Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies . Mol Hum Reprod 14(5) : 317-234

87.

Koh TS (2008) On the a priori identifiability of the two-compartment distributed parameter model from residual tracer data acquired by dynamic contrast-enhanced imaging . IEEE Trans Biomed Eng 55(1) : 340-344

88.

Goh BK, Chow PK, Kesavan S, Yap WM, Wong WK (2008) Outcome after surgical treatment of suspected gastrointestinal stromal tumors involving the duodenum: is limited resection appropriate? . J Surg Oncol 97(5) : 388-391

89.

Zhang ZF, Matsuda D, Khoo SK, Buzzitta K, Block E, Petillo D, Richard S, Anema J, Furge KA, Teh BT (2008) A comparison study reveals important features of agreement and disagreement between summarized DNA and RNA data obtained from renal cell carcinoma. . Mutat ResGen Tox En 657(1) : 77-83

90.

Selvarajan S, Sii LH, Lee A, Yip G, Bay BH, Tan MH, Teh BT, Tan PH (2008) Parafibromin expression in breast cancer: a novel marker for prognostication? . J Clin Pathol 61(1) : 6467

> 105


> 106

91.

Soon SR, Yong WS, Ho GH, Wong CY, Ho BC, Tan PH (2008) Adenoid cystic breast carcinoma: a salivary gland-type tumour with excellent prognosis and implications for management . Pathology 40(4) : 413-415

92.

Goh BK, Chow PK, Kesavan S, Yap WM, Ong HS, Song IC, Eu KW, Wong WK (2008) Intraabdominal schwannomas: a single institution experience. . J Gastrointest Surg 12(4) : 756-760

93.

Wong CM, Ko Y, Chan A (2008) Clinically significant drug-drug interactions between oral anticancer agents and nonanticancer agents: profiling and comparison of two drug compendia . Ann Pharmacother 42(12) : 1737-1748

94.

Ramalingam M, Lau W, Tan T, Fook S, Ngoi F, Cheng C (2008) Asians with localized prostate cancer treated with 3-dimensional conformal radiation therapy and adjuvant hormonal therapy: comparing Phoenix and American Society of Therapeutic Radiology and Oncology (ASTRO) definitions in an Asian population . Urology 71(3) : 506-510

95.

Lim ST, Hee SW, Quek R, Lim LC, Yap SP, Loong SL, Sng I, Tan LH, Ang MK, Ngeow JY, Tham CK, Ngo L, Tan MH, Tao M (2008) Comparative analysis of extra-nodal NK/T-cell lymphoma and peripheral T-cell lymphoma: significant differences in clinical characteristics and prognosis . Eur J Haematol 80(1) : 55-60

96.

Xu Y, Singh J, Premachandran CS, Khairyanto A, Chen KWS, Chen N, Sheppard CJR, Olivo M (2008) Design and development of a 3D scanning MEMS OCT probe using a novel SiOB package assembly . J Micromech Microeng 18(12) : 125005

97.

Singh J, Teo JHS, Xu Y, Premachandran CS, Chen N, Kotlanka R, Olivo M, Sheppard CJR (2008) A two axes scanning SOI MEMS micromirror for endoscopic bioimaging . J Micromech Microeng 18(2) : 025001

98.

Kah JC, Olivo M, Lee CG, Sheppard CJ (2008) Molecular contrast of EGFR expression using gold nanoparticles as a reflectance-based imaging probe . Mol Cell Probe 22(1) : 14-23

99.

Ho J, Tan PH, Hee SW, Wong JS (2008) Underestimation of malignancy of atypical ductal hyperplasia diagnosed on 11-gauge stereotactically guided Mammotome breast biopsy: An Asian breast screen experience . Breast 17(4) : 401-406

100.

Wong ZW, Ang PC, Chowbay B, Wong NS, See HT, Khoo KS (2008) Phase I/II study of gemcitabine with pegylated liposomal doxorubicin as first-line therapy in Asian women with metastatic breast cancer . Breast 17(5) : 517-522

101.

Shord SS, Chew L, Villano J (2008) Evaluation of opioid induced nausea and vomiting in sickle cell disease . Am J Hematol 83(3) : 196-199

102.

Chua C, Zaiden N, Chong KH, See SJ, Wong MC, Ang BT, Tang C (2008) Characterization of a side population of astrocytoma cells in response to temozolomide . J Neurosurg 109(5) : 856-866

103.

Tai BC, De Stavola BL, de Gruttola V, Gebski V, Machin D (2008) First-event or marginal estimation of cause-specific hazards for analysing correlated multivariate failure-time data? . Stat Med 27(6) : 922-936

104.

Hughes S, Barbachano Y, Ashley S, Yap YS, Popat S, Allen M, Della-Rovere UQ, Johnston S, Smith I, O'Brien M (2008) Time trends in the outcome of elderly patients with breast cancer . Breast J 14(2) : 158-163


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

105.

De Silva DA, Woon FP, Gan HY, Chen C, Chang HM, Cameron J, Kingwell B, Wong MC (2008) Arterial stiffness is associated with raised levels of the inflammatory marker erythrocyte sedimentation rate among ischaemic stroke patients . Intern Med J 38(12) : 918-920

106.

Kah JC, Phonthammachai N, Wan RC, Song J, White TJ, Mhaisalkar S, Ahmad IB, Sheppard CJ, Olivo M (2008) Synthesis of gold nanoshells using precursor seed particles prepared from a deposition-precipitation process . Gold Bulletin 41(1) : 23-36

107.

Lindley RI, Wong MC, Multi-Centre Retinal Stroke Study Collaborative Group (2008) Retinal microvascular signs: a key to understanding the underlying pathophysiology of different stroke subtypes? . Int J Stroke 3(4) : 297-305

108.

Lim ST, Hee SW, Quek R, Tao M (2008) Performance status is the single most important prognostic factor in lymphoma patients aged greater than 75 overriding other prognostic factors such as histology . Leuk Lymphoma 49(1) : 149-151

109.

Ngo L, Hee SW, Lim LC, Tao M, Quek R, Yap SP, Loong SL, Sng I, Hwan-Cheong TL, Ang MK, Ngeow JY, Tham CK, Tan MH, Lim ST (2008) Prognostic factors in patients with diffuse large B cell lymphoma: Before and after the introduction of rituximab . Leuk Lymphoma 49(3) : 462-469

110.

Tham CK, Tao M, Quek R, Yap SP, Loong SL, Sng I, Tan LHC, Li HH, Lim ST (2008) Clinical characteristics, prognostic factors and outcomes of Burkitt lymphoma in adult Asians . Leuk Lymphoma 49(4) : 824-827

111.

Loong SL, Hwang JS, Lim ST, Yap SP, Tao M, Chong TW, Tan LH, Huynh H (2008) An EpsteinBarr virus positive natural killer lymphoma xenograft derived for drug testing . Leuk Lymphoma 49(6) : 1161-1167

112.

Wang XD, Deng XY, Chen J, Li JL, Chen X, Zhao LZ, Lu Y, Chowbay B, Su QB, Huang M, Zhou SF (2008) Single nucleotide polymorphisms of the pregnane x receptor gene in Han Chinese and a comparison with other ethnic populations . Pharmacology 81(4) : 350-354

113.

Sarraf-Yazdi S, Mi J, Moeller BJ, Niu X, White RR, Kontos CD, Sullenger BA, Dewhirst MW, Clary BM (2008) Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer . J Surg Res 146(1) : 16-23

114.

Williams RS, Casey PJ, Kamei RK, Buckley EG, Soo KC, Merson MH, Krishnan RK, Dzau VJ (2008) A global partnership in medical education between Duke University and the National University of Singapore . Acad Med 83(2) : 122-127

115.

Wee HL, Fong KY, Tse C, Machin D, Cheung YB, Luo N, Thumboo J (2008) Optimizing the design of visual analogue scales for assessing quality of life: a semi-qualitative study among Chinese-speaking Singaporeans . J Eval Clin Pract 14(1) : 121-125

116.

Ilangovan KR, Yeo R (2008) Unusual presentation of metastatic Crohn's disease . Eur J Obstet Gynecol Reprod Biol 137(2) : 259

117.

Thong PS, Olivo M, Kho KW, Bhuvaneswari R, Chin WW, Ong KW, Soo KC (2008) Immune Response against Angiosarcoma following Lower Fluence Rate Clinical Photodynamic Therapy . J Environ Pathol Toxicol Oncol 27(1) : 35-42

118.

Saw CL, Heng PW, Olivo M (2008) Potentiation of the Photodynamic Action of Hypericin . J Environ Pathol Toxicol Oncol 27(1) : 23-33 > 107


> 108

119.

Lau LC, Lim P, Lim YC, Teng LM, Lim TH, Lim LC, Tan SY, Lim ST, Sanger WG, Tien SL (2008) Occurrence of trisomy 12, t(14;18)(q32;q21), and t(8;14)(q24.1;q11.2) in a patient with B-cell chronic lymphocytic leukemia . Cancer Genet Cytogenet 185(2) : 95-101

120.

Tan SB, Wee J, Wong HB, Machin D (2008) Can external and subjective information ever be used to reduce the size of randomised controlled trials? . Contemp Clin Trials 29(2) : 211219

121.

Chuwa EW, Tan VH, Tan PH, Yong WS, Ho GH, Wong CY (2008) Treatment for ductal carcinoma in situ in an Asian population: outcome and prognostic factors . ANZ J Surg 78(1-2) : 42-48

122.

Chan WH, Cheow PC, Chung AY, Ong HS, Koong HN, Wong WK (2008) Pancreaticoduodenectomy for locally advanced stomach cancer: preliminary results . ANZ J Surg 78(9) : 767-770

123.

Goh BK, Tan YM, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2008) Outcome of Distal Pancreatectomy for Pancreatic Adenocarcinoma . Dig Surg 25(1) : 32-38

124.

Ong LC, Jin Y, Song IC, Yu S, Zhang K, Chow PK (2008) 2-[18F]-2-deoxy-D-glucose (FDG) uptake in human tumor cells is related to the expression of GLUT-1 and hexokinase II . Acta Radiol 49(10) : 1145-1153

125.

Tan JS, Thng CH, Tan PH, Cheng CW, Lau WK, Tan T, Ho JTs, Ching BC (2008) Local experience of endorectal magnetic resonance imaging of prostate with correlation to radical prostatectomy specimens . Ann Acad Med Singapore 37(1) : 40-44

126.

Soon JL, Jeyaraj PR, Agasthian T (2008) Thoracic complications of radiofrequency ablation of recurrent hepatoma . Ann Acad Med Singapore 37(1) : 75-76

127.

Yap SP, Lim WT, Foo KF, Hee SW, Leong SS, Fong KW, Eng P, Hsu AA, Wee J, Agasthian T, Koong HN, Tan EH (2008) Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatin combination followed by surgery in locoregionally advanced non-small cell lung cancer asian experience . Ann Acad Med Singapore 37(5) : 377-382

128.

Chia WK, Ong SY, Toh HC, Hee SW, Choo SP, Poon D, Tay MH, Tan CK, Koo WH, Foo KF (2008) Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma . Ann Acad Med Singapore 37(7) : 554-558

129.

Wee J (2008) 4th FY Khoo Memorial Lecture 2008: Nasopharyngeal Cancer Workgroup--the past, the present and the future. . Ann Acad Med Singapore 37(7) : 606-614

130.

Tan MH, Lee Z, Ng B, Sim ES, Chua YY, Tien M, Ooi CJ (2008) The Tao of bao: a randomised controlled trial examining the effect of steamed bun consumption on night-call inpatient course and mortality . Ann Acad Med Singapore 37(3) : 255-253

131.

De Silva DA, Lee MP, Wong MC, Chang HM, Chen CL (2008) Limb-shaking transient ischemic attack with distal micro-embolic signals and impaired cerebrovascular reactivity using transcranial Doppler . Ann Acad Med Singapore 37(7) : 619-620

132.

De Silva DA, Woon FP, Moe KT, Chen CL, Chang HM, Wong MC (2008) Concomitant coronary artery disease among Asian ischaemic stroke patients . Ann Acad Med Singapore 37(7) : 573575


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

133.

Yeo TC, Chan YH, Low LP, Venketasubramanian N, Lim SC, Tay JC, Tan RS, Eng P, Lingamanaicker J, Wong MC, REACH Investigators (2008) Risk factor profile and treatment patterns of patients with atherothrombosis in Singapore: insight from the REACH Registry . Ann Acad Med Singapore 37(5) : 365-371

134.

Choo SP, Venook AP (2008) Emergence of the Epothilones . Oncology (Williston Park) 22(4) : 424-426

135.

Goh C, Walsh Declan T (2008) Culture, Ethnicity and Illness . Palliative Medicine. Mosby, Inc Part 1. Section B. Chapter 10 :

136.

Sandanaraj E, Lal S, Xiang XQ, Kong MC, Lee LH, Chowbay B (2008) VKORC1 diplotypes, warfarin disposition and dose requirements in Chinese patients . SGH Proceedings 17(1) Suppl : O-CLI (1215)

137.

Chen NK, Wong JS, Kee IH, Lai SH, Thng CH, Ng WH, Ng RT, Tan SY, Lee SY, Tan ME, Sivalingam J, Chow PK, Kon OL (2008) Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model . PLoS ONE 3(3) : e1734

138.

Goh C (2008) Challenges of Cultural Diversity . Supportive Care In Heart Failure. James Beattie and Sarah Goodlin (eds). Oxford University Press Pt3 Chapt 25 : 451-462

139.

Balaji R, Khoo JB, Sittampalam K, Soo KC (2008) CT imaging of malignant metastatic hemangiopericytoma of the parotid gland with histopathological correlation . Cancer Imaging 8 : 186-190

140.

Chin WW, Heng PW, Lim Pl, Lau KO, Olivo M (2008) Membrane transport enhancement of chlorin e6-polyvinylpyrrolidone and its photodynamic efficacy on the chick chorioallantoic model . J Biophoto 1(5) : 395-407

141.

Kon OL, Yip TT, Ho M, Chan WH, Wong WK, Tan SY, Ng WH, Kam SY, Eng AK, Ho P, Viner R, Ong HS, Kumarasinghe MP (2008) The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile . BMC Med Genomics 1(1) : 54

142.

Lee SY, Goh BK, Tan YM, Chung AY, Cheow PC, Chow PK, Wong WK, Ooi LL (2008) Spleenpreserving distal pancreatectomy. . Singapore Med J 49(11) : 883-885

143.

Choo SP, Venook AP (2008) Responding to the rising incidence of hepatocellular carcinoma with targeted therapy . Gastrointest Cancer Res 2(2) : 96-97

144.

Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, Li Y, Khoo SK, Huang D, Qian CN, Zhao P, Dykyma K, Zhang R, Cao B, Yang XJ, Furge K, Williams BO, Teh BT (2008) Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia . PLoS ONE 3(10) : e3581

145.

Ha TC, Starmer F (2008) Investigative Methods and Tools: Developing an Integrated Approach to Critical Thinking, Evidence-based Medicine and Biostatistics . SGH Proceedings 17(3) : 160-163

146.

Choo SP, Venook AP (2008) Hepatic Artery Infusion in the Treatment of Colorectal Cancer Metastases . Curr Colorectal Cancer Rep 4(2) : 106-113

> 109


> 110

147.

Toh ST, Lee CG (2008) Role of the Hepatitis B Virus in Hepatocellular Carcinoma . Hum Cancer Viruses. Principles of Transformation and Pathogenesis. Transl Res Biomed 1 : 94107

148.

Chia SC, Chau YP, Tan YM (2008) Late-onset post-transplant lymphoproliferative disease presenting as massive occult gastrointestinal haemorrhage . Singapore Med J 49(5) : e117120

149.

Morris-Stiff G, Tan YM, Vauthey JN (2008) Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases . Eur J Surg Oncol 34(6) : 609-614

150.

Chan A, Shih V, Chew L (2008) Evolving roles of oncology pharmacists in Singapore: a survey on prescribing patterns of antiemetics for chemotherapy induced nausea and vomiting (CINV) at a cancer centre . J Oncol Pharm Pract 14(1) : 23-29

151.

Machin D, Campbell M, Tan SB, Tan SH (2008) Sample Size Tables for Clinical Studies . Sample Size Tables for Clinical Studies. Wiley-Blackwell : 1-264

152.

Ayad T, Kolb F, De Monès E, Mamelle G, Tan HK, Temam S (2008) The musculo-mucosal facial artery flap: harvesting technique and indications . Ann Chir Plast Esthet 53(6) : 487-494

153.

Sarraf-Yazdi S, Mi J, Dewhirst MW, Clary BM (2008) Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice . Eur J Surg Oncol 34(4) : 476-481


Highlighted Publications for 2009:

National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, FrisĂŠ'e9n J Cell. 2009 Nov 13;139(4):679-92. Abstract Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by protooncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth. Oncogenic pathway combinations predict clinical prognosis in gastric cancer Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim DT, Chan WH, Wong WK, Bowtell D, Yeoh KG, Grabsch H, Boussioutas A, Tan P PLoS Genet. 2009 Oct;5(10):e1000676. Abstract Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancerrelated pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.

> 111


Matrix Metalloproteinase 1 Is Necessary for the Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Human Glioma Ho IA, Chan KY, Ng WH, Guo CM, Hui KM, Cheang P, Lam PY Stem Cells. 2009 Jun;27(6):1366-75. Abstract Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis. Prediction of clinical outcome in multiple lung cancer cohorts by integrative genomics: implications for chemotherapy selection BroĂŤt P, Camilleri-BroĂŤt S, Zhang S, Alifano M, Bangarusamy D, Battistella M, Wu Y, Tuefferd M, RĂŠgnard JF, Lim E, Tan P, Miller LD Cancer Res. 2009 Feb 1;69(3):1055-62. Abstract The role of adjuvant chemotherapy in patients with stage IB non-small-cell lung cancer (NSCLC) is controversial. Identifying patient subgroups with the greatest risk of relapse and, consequently, most likely to benefit from adjuvant treatment thus remains an important clinical challenge. Here, we hypothesized that recurrent patterns of genomic amplifications and deletions in lung tumors could be integrated with gene expression information to establish a robust predictor of clinical outcome in stage IB NSCLC. Using high-resolution microarrays, we generated tandem DNA copy number and gene expression profiles for 85 stage IB lung adenocarcinomas/large cell carcinomas. We identified specific copy number alterations linked to relapse-free survival and selected genes within these regions exhibiting copy number-driven expression to construct a novel integrated signature (IS) capable of predicting clinical outcome in this series (P = 0.02). Importantly, the IS also significantly predicted clinical outcome in two other independent stage I NSCLC cohorts (P = 0.003 and P = 0.025), showing its robustness. In contrast, a more conventional molecular predictor based solely on gene expression, while capable of predicting outcome in the initial series, failed to significantly predict outcome in the two independent data sets. Our results suggest that recurrent copy number alterations, when combined with gene expression information, can be successfully used to create robust predictors of clinical outcome in early-stage NSCLC. The utility of the IS in identifying early-stage NSCLC patients as candidates for adjuvant treatment should be further evaluated in a clinical trial.

> 112


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling Sung WK, Lu Y, Lee CW, Zhang D, Ronaghi M, Lee CG J Biol Chem. 2009 Aug 14;284(33):21941-54. Abstract The hepatitis B-X (HBx) protein is strongly associated with hepatocellular carcinoma. It is implicated not to directly cause cancer but to play a role in hepatocellular carcinoma as a co-factor. The oncogenic potential of HBx primarily lies in its interaction with transcriptional regulators resulting in aberrant gene expression and deregulated cellular pathways. Utilizing ultraviolet irradiation to simulate a tumor-initiating event, we integrated chip-based chromatin immunoprecipitation (ChIP-chip) with expression microarray profiling and identified 184 gene targets directly deregulated by HBx. One-hundred forty-four transcription factors interacting with HBx were computationally inferred. We experimentally validated that HBx interacts with some of the predicted transcription factors (pTF) as well as the promoters of the deregulated target genes of these pTFs. Significantly, we demonstrated that the pTF interacts with the promoters of the deregulated HBx target genes and that deregulation by HBx of these HBx target genes carrying the pTF consensus sequences can be reversed using pTF small interfering RNAs. The roles of these deregulated direct HBx target genes and their relevance in cancer was inferred via querying against biogroup/cancerrelated microarray databases using web-based NextBio(TM) software. Six pathways, including the JakSTAT pathway, were predicted to be significantly deregulated when HBx binds indirectly to direct target gene promoters. In conclusion, this study represents the first ever demonstration of the utilization of ChIPchip to identify deregulated direct gene targets from indirect protein-DNA binding as well as transcriptional factors directly interacting with HBx. Increased knowledge of the gene/transcriptional factor targets of HBx will enhance our understanding of the role of HBx in hepatocellular carcinogenesis and facilitate the design of better strategies in combating hepatitis B virus-associated hepatocellular carcinoma.

> 113


1.

Lindley RI, Wang JJ, Wong MC, Mitchell P, Liew G, Hand P, Wardlaw J, De Silva DA, Baker M, Rochtchina E, Chen C, Hankey GJ, Chang HM, Fung VS, Gomes L, Wong TY; Multi-Centre Retina and Stroke Study (MCRS) Collaborative Group (2009) Retinal microvasculature in acute lacunar stroke: a cross-sectional study . Lancet Neurol 8(7) : 628-634

2.

Quek R, Morgan JA, George S, Butrynski JE, Polson K, Meyer F, Demetri GD, Block SD (2009) Small molecule tyrosine kinase inhibitor and depression . J Clin Oncol 27(2) : 312-313

3.

Koo YX, Tan DS, Tan IB, Quek R, Tao M, Lim ST (2009) Risk of hepatitis B virus reactivation in patients who are hepatitis B surface antigen negative/antibody to hepatitis B core antigen positive and the role of routine antiviral prophylaxis . J Clin Oncol 27(15) : 2570-2571

4.

Morgan JA, Quek R, George S, Block SD, Demetri GD (2009) Reply to W.F. Pirl et al . J Clin Oncol 27(23) : e51

5.

Tan MH, Tan CS, Lim WY (2009) Race to report: are vascular endothelial growth factor genetic polymorphisms associated with outcome in advanced breast cancer patients treated with Paclitaxel plus bevacizumab? . J Clin Oncol 27(8) : 1342

6.

Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, Yong WP, Chen CS, Lee SC, Wong J, Lim R, Sukri N, Lim SE, Ong AB, Steinberg J, Gupta N, Pradhan R, Humerickhouse R, Goh BC (2009) Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies . J Clin Oncol 27(28) : 4718-4726

7.

Koo YX, Tan DS, Tan IB, Tao M, Lim ST (2009) Hepatitis B virus reactivation in a patient with resolved hepatitis B virus infection receiving maintenance rituximab for malignant B-cell lymphoma . Ann Intern Med 150(9) : 655-656

8. 9.

> 114

Wee J, Anderson BO, Corry J, D'Cruz A, Soo KC, Qian CN, Chua DT, Hicks RJ, Goh CH, Khoo JB, Ong SC, Forastiere AA, Chan AT (2009) Management of the neck after chemoradiotherapy for head and neck cancers in Asia: consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1086-1092

10.

Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin MW, Koo WH (2009) Management of hepat ocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 11111118

11.

Soo RA, Anderson BO, Cho BC, Yang CH, Liao M, Lim WT, Goldstraw P, Mok TS (2009) Firstline systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1102-1110

12.

Kwong YL, Anderson BO, Advani R, Kim WS, Levine AM, Lim ST (2009) Management of T-cell and natural-killer-cell neoplasms in Asia: consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1093-1101

13.

Wong NS, Anderson BO, Khoo KS, Ang PT, Yip CH, Lu YS, Voravud N, Shao ZM, Pritchard KI (2009) Management of HER2-positive breast cancer in Asia: consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1077-1085

14.

Yap KY, Chan A, Chui WK (2009) Improving pharmaceutical care in oncology by pharmacoinformatics: the evolving role of informatics and the internet for drug therapy . Lancet Oncol 10(10) : 1011-1019


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

15.

Narasimhalu K, Ang S, De Silva DA, Wong MC, Chang HM, Chia KS, Auchus AP, Chen C (2009) Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort . Neurology 73(22) : 1866-1872

16.

Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC (2009) AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC) . J Hepatol 15(24) : 7726-7736

17.

Chong YK, Toh TB, Zaiden N, Poonepalli A, Leong SH, Ee Ling Ong C, Yu Y, Tan P, See SJ, Ng WH, Ng I, Hande MP, Kon OL, Ang BT, Tang C (2009) Cryopreservation of Neurospheres derived from Human Glioblastoma Multiforme . Stem Cells 27(1) : 29-39

18.

Qian CN, Furge KA, Knol J, Huang D, Chen J, Dykema KJ, Kort EJ, Massie A, Khoo SK, Vanden Beldt K, Resau JH, Anema J, Kahnoski RJ, Morreau H, Camparo P, Comperat E, Sibony M, Denoux Y, Molinie V, Vieillefond A, Eng C, Williams BO, Teh BT (2009) Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models . Cancer Res 69(21) : 8256-8264

19.

Fan HM, Yi JB, Yang Y, Kho KW, Tan HR, Shen ZX, Ding J, Sun XW, Olivo M, Feng YP (2009) Single-Crystalline MFe(2)O(4) Nanotubes/Nanorings Synthesized by Thermal Transformation Process for Biological Applications . ACS Nano 3(9) : 2798-2808

20.

Baum N, Schiene-Fischer C, Frost M, Schumann M, Sabapathy K, Ohlenschl채ger O, Grosse F, Schlott B (2009) The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis . Oncogene 28(44) : 3915-3925

21.

Ong DC, Ho YM, Rudduck C, Chin K, Kuo WL, Lie DK, Chua CL, Tan PH, Eu KW, Seow-Choen F, Wong CY, Hong GS, Gray JW, Lee AS (2009) LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer . Oncogene 28(47) : 4189-4200

22.

Lee P, Cheah FK, Huang J, Poon D, Loo CM (2009) A suspicious clot . Thorax 64(11) : 1011

23.

De Silva DA, Liew G, Wong MC, Chang HM, Chen C, Wang JJ, Baker ML, Hand PJ, Rochtchina E, Liu EY, Mitchell P, Lindley RI, Wong TY (2009) Retinal vascular caliber and extracranial carotid disease in patients with acute ischemic stroke: the Multi-Centre Retinal Stroke (MCRS) study . Stroke 40(12) : 3695-3699

24.

De Silva DA, Chang HM, Woon FP, Chen CP, Wong MC (2009) Ischemic stroke in ethnic South Asians . Stroke 40(10) : e594

25.

Kasiman K, Eikelboom JW, Hankey GJ, Lee SP, Lim JP, Lee JH, Chang HM, Wong MC, Chen CP (2009) Ethnicity does not affect the homocysteine-lowering effect of B-vitamin therapy in Singaporean stroke patients . Stroke 40(6) : 2209-2211

26.

Srinivasan BS, Doostzadeh J, Absalan F, Mohandessi S, Jalili R, Bigdeli S, Wang J, Mahadevan J, Lee CG, Davis RW, William Langston J, Ronaghi M (2009) Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease . Hum Mutat 30(2) : 228-238

> 115


> 116

27.

Ong KW, Teo M, Lee V, Ong D, Lee A, Tan CS, Vathsala A, Toh HC (2009) Expression of EBV Latent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBVPositive Smooth Muscle Tumors: Clinical and Therapeutic Implications . Clin Cancer Res 15(17) : 5350-5358

28.

Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, Phoon YP, Soe Y, Tan SH, Hee SW, Foo KF, Ong SY, Koo WH, Zocca MB, Claesson MH (2009) Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients . Clin Cancer Res 15(24) : 7726-7736

29.

Macher-Goeppinger S, Aulmann S, Tagscherer KE, Wagener N, Haferkamp A, Penzel R, Brauckhoff A, Hohenfellner M, Sykora J, Walczak H, Teh BT, Autschbach F, Herpel E, Schirmacher P, Roth W (2009) Prognostic value of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors in renal cell cancer . Clin Cancer Res 15(2) : 650-659

30.

Chew HC, Lee CH, Cheah FK, Lim ST, Loo CM (2009) Cardiac tumor and renal involvement in a nonsmoker with centrilobular pulmonary nodules . Chest 135(4) : 1102-1106

31.

Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O, Marsh DJ (2009) Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma . J Clin Endocrinol Metab 94(2) : 434-441

32.

Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2009) The effect of photodynamic therapy on tumor angiogenesis . Cell Mol Life Sci 66(14) : 2275-2283

33.

Tan EK, Lee J, Chen CP, Wong MC, Zhao Y (2009) Case control analysis of LRRK2 Gly2385Arg in Alzheimer's disease . Neurobiol Aging 30(3) : 501-502

34.

Samuel M, Chow PK, Chan SY, Machin D, Soo KC (2009) Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma . Cochrane Database Syst Rev (1) : CD001199

35.

Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R (2009) Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer . Ann Oncol 20(7) : 1249-1256

36.

Ngeow JY, Quek R, Ng DC, Hee SW, Tao M, Lim LC, Tan YH, Lim ST (2009) High SUV uptake on FDG-PET/CT predicts for an aggressive B-cell lymphoma in a prospective study of primary FDG-PET/CT staging in lymphoma . Ann Oncol 20(9) : 1543-1547

37.

Wong MC, Choo SP, Tan EH (2009) Travel warning with capecitabine . Ann Oncol 20(7) : 1281

38.

Shih V, Chiang JY, Chan A (2009) Complementary and alternative medicine (CAM) usage in Singaporean adult cancer patients . Ann Oncol 20(4) : 752-757

39.

Koh V, Goh BK, Goh AS, Chow PK (2009) Utility of Positron Emission Tomography/Computed Tomography in the Detection of Malignancy Within a Choledochal Cyst . Clin Gastroenterol Hepatol 7(4) : e17-e18


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

40.

Pearson T, Giffard P, Beckstrom-Sternberg S, Auerbach R, Hornstra H, Tuanyok A, Price EP, Glass MB, Leadem B, Beckstrom-Sternberg JS, Allan GJ, Foster JT, Wagner DM, Okinaka RT, Sim SH, Pearson O, Wu Z, Chang J, Kaul R, Hoffmaster AR, Brettin TS, Robison RA, Mayo M, Gee JE, Tan P, Currie BJ, Keim P (2009) Phylogeographic reconstruction of a bacterial species with high levels of lateral gene transfer . BMC Biol 7 : 78

41.

Zhou SF, Liu JP, Chowbay B (2009) Polymorphism of human cytochrome P450 enzymes and its clinical impact. . Drug Metab Rev 41(2) : 89-295

42.

Qian CN, Huang D, Wondergem B, Teh BT (2009) Complexity of tumor vasculature in clear cell renal cell carcinoma . Cancer 115(S10) : 2282-2289

43.

Atkins MB, Bukowski RM, Escudier BJ, Figlin RA, Hudes GH, Kaelin WG Jr, Linehan WM, McDermott DF, Mier JW, Pedrosa I, Rini BI, Signoretti S, Sosman JA, Teh BT, Wood CG, Zurita AJ, King L (2009) Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference . Cancer 115(10 Suppl) : 2247-2251

44.

Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, Nederlof P, Yu Q, Jonkers J, van Lohuizen M, Pietersen AM (2009) BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3deazaneplanocin A . Breast Cancer Res 11(4) : R63

45.

Tham CK, Poon D, Li HH, Tan MH, Choo SP, Foo KF (2009) Gastrointestinal stromal tumour in the elderly . Crit Rev Oncol Hematol 70(3) : 256-261

46.

Huynh H, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, Poon D, Ngo VC, Tran E (2009) RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma . J Cell Mol Med 13(7) : 1371-1380

47.

Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC (2009) Sorafenib and Rapamycin Induce Growth Suppression in Mouse Models of Hepatocellular Carcinoma. . J Cell Mol Med 13(8B) : 2673-2683

48.

Wang Y, Lee CG (2009) MicroRNA and cancer - focus on apoptosis. . J Cell Mol Med 13(1) : 12-23

49.

Huynh H, Ngo VC, Choo SP, Poon D, Koong HN, Thng CH, Toh HC, Zheng L, Ong LC, Jin Y, Song IC, Chang AP, Ong HS, Chung AY, Chow PK, Soo KC (2009) Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma . Curr Cancer Drug Targets 9(6) : 738-747

50.

De Silva DA, Woon FP, Gan HY, Chen CP, Chang HM, Koh TH, Kingwell BA, Cameron JD, Wong MC (2009) Arterial stiffness is associated with intracranial large artery disease among ethnic Chinese and South Asian ischemic stroke patients . J Hypertens 27(7) : 1453-1458

51.

Huynh H, Lee JW, Chow PK, Ngo VC, Lew GB, Lam IW, Ong HS, Chung AY, Soo KC (2009) Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor . Mol Cancer Ther 8(1) : 152-159

52.

Yang S, Ngo VC, Lew GB, Chong LW, Lee SS, Ong WJ, Lam WL, Thng CH, Koong HN, Ong HS, Chung A, Chow P, Lee J, Soo KC, Huynh H (2009) AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer . Mol Cancer Ther 8(9) : 2537-2545

> 117


> 118

53.

Ho YM, Sun YJ, Wong SY, Lee AS (2009) Contribution of dfrA and inhA mutations to the detection of isoniazid-resistant Mycobacterium tuberculosis isolates . Antimicrob Agents Chemother 53(9) : 4010-4012

54.

Tan FL, Ooi A, Huang D, Wong JC, Qian CN, Chao C, Ooi L, Tan YM, Chung A, Cheow PC, Zhang Z, Petillo D, Yang XJ, Teh BT (2009) p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion . Int J Cancer 126(10) : 2353-2361

55.

Tham IW, Hee SW, Yeo R, Salleh PB, Lee J, Tan T, Fong KW, Chua ET, Wee J (2009) Treatment of Nasopharyngeal Carcinoma Using Intensity-Modulated Radiotherapy-The National Cancer Centre Singapore Experience . Int J Radiat Oncol Biol Phys 75(5) : 1481-1486

56.

Hui Z, Tretiakova M, Zhang Z, Li Y, Wang X, Zhu JX, Gao Y, Mai W, Furge K, Qian CN, Amato R, Butler EB, Teh BT, Teh BS (2009) Radiosensitization by inhibiting STAT1 in renal cell carcinoma . Int J Radiat Oncol Biol Phys 73(1) : 288-295

57.

Lim EH, Zhang SL, Li JL, Yap WS, Howe TC, Tan BP, Lee YS, Wong D, Khoo KL, Seto KY, Tan L, Agasthian T, Koong HN, Tam J, Tan C, Caleb M, Chang A, Ng A, Tan P (2009) Using whole genome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR, KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC). . J Thorac Oncol 4(1) : 12-21

58.

Tham CK, Choo SP, Lim WT, Toh CK, Leong SS, Tan SH, Li HH, Tan EH (2009) Gefitinib in Combination with Gemcitabine and Carboplatin in Never Smokers with Non-small Cell Lung Carcinoma: A Retrospective Analysis . J Thorac Oncol 4(8) : 988-993.

59.

Pramono ZA, Tan CL, Seah IA, See JS, Kam SY, Lai PS, Yee WC (2009) Identification and characterisation of human dysferlin transcript variants: implications for dysferlin mutational screening and isoforms. . Hum Genet 125(4) : 413-420

60.

Tay WL, Yip GW, Tan PH, Matsumoto K, Yeo R, Ng TP, Kumar SD, Tsujimoto M, Bay BH (2009) Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer . Mod Pathol 22(2) : 282-290

61.

Thong PS, Olivo M, Chin WW, Bhuvaneswari R, Mancer K, Soo KC (2009) Clinical application of fluorescence endoscopic imaging using hypericin for the diagnosis of human oral cavity lesions . Br J Cancer 101(9) : 1580-1584

62.

Wang YC, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo SP, Zuraek MB, Gogia R, Lynn FC, German MS, Bergsland EK, Donner DB, Warren RS, Nakakura EK (2009) Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors . Endocr Relat Cancer 16(1) : 267-279

63.

Khoo SK, Pendek R, Nickolov R, Luccio-Camelo DC, Newton TL, Massie A, Petillo D, Menon J, Cameron D, Teh BT, Chan SP (2009) Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma . Endocr Relat Cancer 16(3) : 1057-1063

64.

Shin S, Asano T, Yao Y, Zhang R, Claret FX, Korc M, Sabapathy K, Menter DG, Abbruzzese JL, Reddy SA (2009) Activator Protein-1 Has an Essential Role in Pancreatic Cancer Cells and Is Regulated by a Novel Akt-Mediated Mechanism . Mol Cancer Res 7(5) : 745-754


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

65.

Kang KB, Zhu CJ, Yong SK, Gao QH, Wong MC (2009) Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy . Mol Cancer 8(1) : 66

66.

Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2009) Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response . Mol Cancer 8(1) : 94

67.

Lee SC, Xu X, Lim YW, Iau P, Sukri N, Lim SE, Yap HL, Yeo WL, Tan P, Tan SH, McLeod H, Goh BC (2009) Chemotherapy-induced tumor gene expression changes in human breast cancers . Pharmacogenet Genomics 19(3) : 181-192

68.

Lee SC, Xu X, Chng WJ, Watson M, Lim YW, Wong CI, Iau P, Sukri N, Lim SE, Yap HL, Buhari SA, Tan P, Guo J, Chuah B, McLeod HL, Goh BC (2009) Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer . Pharmacogenet Genomics 19(11) : 833-842

69.

Tan P (2009) Germline polymorphisms as modulators of cancer phenotypes . BMC Med 6 : 27

70.

Tan IB, Padhy AK, Thng CH, Osmany S, Magsombol B, Ho YH, Tham CK, Quek R, Tao M, Lim ST (2009) Intensely hypermetabolic extra-axial brainstem tumor in Erdheim-chester disease . Clin Nucl Med 34(9) : 604-607

71.

Pang GS, Wang J, Wang Z, Lee CG (2009) Predicting potentially functional SNPs in drugresponse genes . Pharmacogenomics 10(4) : 639-653

72.

Pang GS, Wang J, Wang Z, Goh C, Lee CG (2009) The G allele of SNP E1/A118G at the muopioid receptor gene locus shows genomic evidence of recent positive selection . Pharmacogenomics 10(7) : 1101-1109

73.

Wang Z, Sew PH, Chong SS, Lee CG (2009) Realtime exonuclease-mediated allelic discrimination (READ): a simple homogeneous genotyping assay for SNPs at the ABC gene loci . Pharmacogenomics 10(12) : 1995-2001

74.

Toh HC, Sun L, Soe Y, Wu Y, Phoon YP, Chia WK, Wu J, Wong KY, Tan P (2009) G-CSF induces a potentially tolerant gene and immunophenotype profile in T cells in vivo . Clin Immunol 132(1) : 83-92

75.

Begum SM, Jara-Lazaro AR, Thike AA, Tse GM, Wong JS, Ho JT, Tan PH (2009) Mucin extravasation in breast core biopsies--clinical significance and outcome correlation . Histopathology 55(5) : 609-617

76.

Puan KJ, Low JS, Tan T, Wee J, Tan EH, Fong KW, Chua ET, Jin C, Giner JL, Morita CT, Goh CH, Hui KM (2009) Phenotypic and functional alterations of Vgamma2Vdelta2 T cell subsets in patients with active nasopharyngeal carcinoma . Cancer Immunol Immunother 58(7) : 10951107

77.

Hui KM (2009) Human hepatocellular carcinoma: Expression profiles-based molecular interpretations and clinical applications. . Cancer Lett 286(1) : 96-102

78.

Chua TC, Liauw W, Robertson G, Chia WK, Soo KC, Alobaid A, Al-Mohaimeed K, Morris DL (2009) Towards randomized trials of cytoreductive surgery using peritonectomy and hyperthermic intraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis . Gynecol Oncol 114(1) : 137-139

> 119


> 120

79.

Kvistborg P, Bechmann CM, Pedersen AW, Toh HC, Claesson MH, Zocca MB (2009) Comparison of monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lungcancer patients and healthy donors . Vaccine 28(2) : 542-547

80.

Koh TS, Thng CH, Hartono S, Lee PS, Choo SP, Poon D, Toh HC, Bisdas S (2009) Dynamic contrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modeling . 19(5) : 1184-1196

81.

Tan DS, Thomas GV, Garrett MD, Banerji U, de Bono JS, Kaye SB, Workman P (2009) Biomarkerdriven early clinical trials in oncology: a paradigm shift in drug development . Cancer J 15(5) : 406-420

82.

Ramalingam N, Liu HB, Dai CC, Jiang Y, Wang H, Wang Q, Hui KM, Gong HQ (2009) Real-time PCR array chip with capillary-driven sample loading and reactor sealing for point-of-care applications . Biomed Microdevices 11(5) : 1007-1020

83.

Ang P, Lim IH, Yong RY, Lee AS (2009) A molecular approach for identifying individuals with Li-Fraumeni syndrome who have a limited family history. . Clin Genet 75(3) : 294-297

84.

Dong H, Gong YD, Paulose V, Shum P, Olivo M (2009) Effect of input states of polarization on the measurement error of Mueller matrix in a system having small polarization-dependent loss or gain . Opt Express 17(15) : 13017-13030

85.

Dong H, Gong YD, Paulose V, Shum P, Olivo M (2009) Optimum input states of polarization for Mueller matrix measurement in a system having finite polarization-dependent loss or gain . Opt Express 17(25) : 23044-23057

86.

Ranganath SH, Kee I, Krantz WB, Chow PK, Wang CH (2009) Hydrogel Matrix Entrapping PLGA-Paclitaxel Microspheres: Drug Delivery with Near Zero-Order Release and Implantability Advantages for Malignant Brain Tumour Chemotherapy . Pharmaceut Res 26(9) : 2101-2114

87.

Linn YC, Lau SK, Liu BH, Ng LH, Yong HX, Hui KM (2009) Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell . Immunology 126(3) : 423-435

88.

Chan A, Tan SH, Wong CM, Yap KY, Ko Y (2009) Clinically significant drug-drug interactions between oral anticancer agents and nonanticancer agents: A delphi survey of oncology pharmacists . Clin Ther 31(Pt2) : 2379-2386

89.

Purushotham S, Chang PE, Rumpel H, Kee IH, Ng RT, Chow PK, Tan CK, Ramanujan RV (2009) Thermoresponsive core-shell magnetic nanoparticles for combined modalities of cancer therapy . Nanotechnology 20(30) : 305101

90.

Liu HB, Ramalingam N, Jiang Y, Dai CC, Hui KM, Gong HQ (2009) Rapid distribution of a liquid column into a matrix of nanoliter wells for parallel real-time quantitative PCR . Sens Actuators B Chem 35(2) : 671-677

91.

Cheung YB, Thumboo J, Gao F, Ng GY, Pang G, Koo WH, Sethi VK, Wee J, Goh C (2009) Mapping the English and Chinese Versions of the Functional Assessment of Cancer Therapy-General to the EQ-5D Utility Index . Value Health 12(2) : 371 - 376

92.

Sie L, Loong S, Tan EK (2009) Utility of lymphoblastoid cell lines . J Neurosci Res 87(9) : 19531959


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

93.

Gao F, Ng GY, Cheung YB, Thumboo J, Pang G, Koo WH, Sethi VK, Wee J, Goh C (2009) The Singaporean English and Chinese versions of the EQ-5D achieved measurement equivalence in cancer patients . J Clin Epidemiol 62(2) : 206-213

94.

Ang MK, Hee SW, Quek R, Yap SP, Loong SL, Tan L, Tao M, Lim ST (2009) Presence of a highgrade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is not associated with an adverse prognosis . Ann Hematol 88(5) : 417-424

95.

Kah JC, Wong KY, Neoh KG, Song JH, Fu JW, Mhaisalkar S, Olivo M, Sheppard CJ (2009) Critical parameters in the pegylation of gold nanoshells for biomedical applications: An in vitro macrophage study . J Drug Target 17(3) : 181-193

96.

Markus HS, Siegel JE, Topakian R, Schaafsma A, Reihill S, Cullinane M, McCorie H, Morgan E, Kwon S, Jones K, Keating R, Shipley M, Davies A, Qu SB, Czlonkowskia A, Rozenfeld A, Piorkowska A, Skowronska M, Fitzgerald D, McMahon N, Sitzer M, Singer O, Baskerville P, Deane C, Goss D, Naylor R, Walker J, Wong L, Fokkens A, Brown M, Hao SQ, Liu R, Lee MP, Streifler J, Sabah T, Brusa G, Montano V, Ottonello GA, Wong MC, Chen CP (2009) The Asymptomatic Carotid Emboli Study: study design and baseline results . Int J Stroke 4(5) : 398-405

97.

Loa J, Chow PK, Zhang K (2009) Studies of structure-activity relationship on plant polyphenolinduced suppression of human liver cancer cells . Cancer Chemother Pharmacol 63(6) : 10071916

98.

Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM (2009) Modulation of ironregulatory genes in human hepatocellular carcinoma and its physiological consequences . Exp Biol Med (Maywood) 234(6) : 693-702

99.

Lai GG, Lim ST, Tao M, Chan A, Li H, Quek R (2009) Late-onset neutropenia following RCHOP chemotherapy in diffuse large B-cell lymphoma . Am J Hematol 84(7) : 414-417

100.

Zhu X, Rivera A, Golub MS, Peng J, Sha Q, Wu X, Song X, Kumarathasan P, Ho M, Redman CM, Lee S (2009) Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel) . Am J Hematol 84(8) : 492-498

101.

Sandanaraj E, Lal S, Cheung YB, Xiang X, Kong MC, Lee LH, Ooi LL, Chowbay B (2009) VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients . Drug Metab Pharmacokinet 24(4) : 365-375

102.

Loong SL, Hwang JS, Li HH, Wee J, Yap SP, Chua ML, Fong KW, Tan T (2009) Negligible or weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01) . Radiat Oncol 4(1): : 23

103.

De Silva DA, Ancalan M, Doshi K, Chang HM, Wong MC, Chen C (2009) Intracranial large artery disease in Alzheimer's disease and vascular dementia among ethnic Asians . Eur J Neurol 16(5) : 643-645

104.

Liu J, Saw CL, Olivo M, Sudhaharan T, Ahmed S, Heng PW, Wohland T (2009) Study of interaction of hypericin and its pharmaceutical preparation by fluorescence techniques. . J Biomed Opt 14(1) : 014003

105.

Kah JC, Olivo M, Chow TH, Song KS, Koh KZ, Mhaisalkar S, Sheppard CJ (2009) Control of optical contrast using gold nanoshells for optical coherence tomography imaging of mouse xenograft tumor model in vivo . J Biomed Opt 14(5) : 054015 > 121


> 122

106.

Ong LC, Song IC, Jin Y, Kee IH, Siew E, Yu S, Thng CH, Huynh H, Chow PK (2009) Effective inhibition of xenografts of hepatocellular carcinoma (HepG2) by rapamycin and bevacizumab in an intrahepatic model . Mol Imaging Biol 11(5) : 334-342

107.

Shih V, Wan HS, Chan A (2009) Clinical predictors of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adjuvant doxorubicin and cyclophosphamide . Ann Pharmacother 43(3) : 444-452

108.

Tan EH, Chan A (2009) Evidence-Based Treatment Options for the Management of Skin Toxicities Associated with Epidermal Growth Factor Receptor Inhibitors . Ann Pharmacother 43(10) : 1658-1666

109.

Petillo D, Kort EJ, Anema J, Furge KA, Yang XJ, Teh BT (2009) MicroRNA profiling of human kidney cancer subtypes . Int J Oncol 35(1) : 109-114

110.

Goh BK, Chow PK, Kesavan SM, Yap WM, Chung AY, Wong WK (2009) A Single-Institution Experience with Eight CD117-Positive Primary Extragastrointestinal Stromal Tumors: Critical Appraisal and a Comparison with Their Gastrointestinal Counterparts . J Gastrointest Surg 13(6) : 1094-1098

111.

Goh BK, Ooi LL, Cheow PC, Tan YM, Ong HS, Chung AY, Chow PK, Wong WK, Soo KC (2009) Accurate Preoperative Localization of Insulinomas Avoids the Need for Blind Resection and Reoperation: Analysis of a Single Institution Experience with 17 Surgically Treated Tumors over 19 Years . J Gastrointest Surg 13(6) : 1071-1077

112.

De Silva DA, Woon FP, Chen CL, Chang HM, Wong MC (2009) Ethnic South Asian ischaemic stroke patients have a higher prevalence of a family history of vascular disease compared to age, gender and diabetes-matched ethnic Chinese subjects . J Neurol Sci 285(1-2) : 118120

113.

De Silva DA, Woon FP, Chen C, Chang HM, Wong MC (2009) Serum erythrocyte sedimentation rate is higher among ethnic South Asian compared to ethnic Chinese ischemic stroke patients. Is this attributable to metabolic syndrome or central obesity . J Neurol Sci 276(12) : 126-129.

114.

Tan CY, Chong YS, Loganath A, Chan YH, Ravichandran J, Lee CG, Chong SS (2009) Possible Gene-Gene Interaction of KIR2DL4 With its Cognate Ligand HLA-G in Modulating Risk for Preeclampsia . Reprod Sci 16(12) : 1135-1143

115.

Chua ML, Ong SC, Wee J, Ng DC, Gao F, Tan T, Fong KW, Chua ET, Khoo JB, Low JS (2009) Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngeal carcinoma . Head Neck 31(3) : 346-354

116.

Iyer NG, Clark JR, Murali R, Gao K, O'Brien CJ (2009) Outcomes following parotidectomy for metastatic squamous cell carcinoma with microscopic residual disease: implications for facial nerve preservation . Head Neck 31(1) : 21-27

117.

Tham IW, Hee SW, Yap SP, Tuan JK, Wee J (2009) Retropharyngeal nodal metastasis related to higher rate of distant metastasis in patients with N0 and N1 nasopharyngeal cancer . Head Neck 31(4) : 468-474

118.

Yeo R, Fong KW, Hee SW, Chua ET, Tan T, Wee J (2009) Brachytherapy boost for T1/T2 nasopharyngeal carcinoma . Head Neck 31(12) : 1610-1618


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

119.

Kanesvaran R, Tao M, Tan IB, Tan DS, Ng DCE, Lim ST (2009) Malignant arrhythmia: A case report of nasal NK/T-cell lymphoma with cardiac involvement . Acta Oncol 48(4) : 637-639

120.

Tang T, Tay KY, Chai J, Agarwal A, Low J, Lee EL, Chuah KL, Sittampalan KS, Wong CF, Dalmau J, Ngeow JY, Soh LT, Tan MH (2009) A multimodality approach to reversible paraneoplastic encephalitis associated with ovarian teratomas . Acta Oncol 48(7) : 1079-1082

121.

Koo YX, Tan DS, Tan IB, Quek R, Tao M, Lim ST (2009) "Anti-HBc alone" in human immunodeficiency virus-positive and immuno-suppressed lymphoma patients . World J Gastroenterol 15(30) : 3834-3835

122.

Abdullah SA, Gupta T, Jaafar KA, Chung YF, Ooi LL, Mesenas SJ (2009) Ampullary carcinoma: effect of preoperative biliary drainage on surgical outcome . World J Gastroenterol 15(23) : 2908-2912

123.

Li H, Ha TC, Tai BC (2009) XRCC1 Gene Polymorphisms and Breast Cancer Risk in Different Populations: A Meta-Analysis . Breast 18(3) : 183-191

124.

Lambert C, Berlin I, Lee TL, Hee SW, Tan AS, Picard D, Han JS (2009) A Standardized Transcutaneous Electric Acupoint Stimulation for Relieving Tobacco Urges in Dependent Smokers . Evid Based Complement Alternat Med : 1-9

125.

Quek R, George S (2009) Gastrointestinal stromal tumor: a clinical overview . Hematol Oncol Clin North Am 23(1) : 69-78, viii

126.

Koh TH, Sng LH, Yuen SM, Thomas CK, Tan PL, Tan SH, Wong NS (2009) Streptococcal Cellulitis Following Preparation of Fresh Raw Seafood . Zoonoses Public Health 56(4) : 206-208

127.

Leong QM, Lai HK, Lo RG, Teo TK, Goh A, Chow PK (2009) Radiation Dermatitis following Radioembolization for Hepatocellular Carcinoma: A Case for Prophylactic Embolization of a Patent Falciform Artery . J Vasc Interv Radiol 20(6) : 833-836

128.

Pua U, Low SC, Tan YM, Lim KH (2009) Combined hepatocellular and cholangiocarcinoma with sarcomatoid transformation: radiologic-pathologic correlation of a case . Hepatol Int 3(4) : 587-592

129.

Kho KW, Stoddart PR, Harris M, Mazzolini AP (2009) Confocal fluorescence polarization microscopy for linear unmixing of spectrally similar labels . Micron 40(2) : 212-217

130.

Chuwa EW, Yeo AW, Koong HN, Wong CY, Yong WS, Tan PH, Ho JT, Wong JS, Ho GH (2009) Early detection of breast cancer through population-based mammographic screening in Asian women: a comparison study between screen-detected and symptomatic breast cancers . Breast J 15(2) : 133-139

131.

Lim WT, Chuah KL, Leong SS, Tan EH, Toh CK (2009) Assessment of human papillomavirus and Epstein-Barr virus in lung adenocarcinoma . Oncol Rep 21(4) : 971-975

132.

Kah JC, Chow TH, Ng BK, Razul SG, Olivo M, Sheppard CJ (2009) Concentration dependence of gold nanoshells on the enhancement of optical coherence tomography images: a quantitative study . Appl Optics 48(10) : D96-D108

133.

Iyer NG, Clark JR, Ashford BG (2009) Internal mammary artery perforator flap for head and neck reconstruction . ANZ J Surg 79(11) : 799-803

> 123


> 124

134.

Bisdas S, Baghi M, Wagenblast J, Bisdas T, Thng CH, Mack MG, Koh TS, Ernemann U (2009) Tracer kinetics analysis of dynamic contrast-enhanced CT and MR data in patients with squamous cell carcinoma of the upper aerodigestive tract: comparison of the results . Clin Physiol Funct Imaging 29(5) : 339-346

135.

Yap KY, Tay WL, Chui WK, Chan A (2009) Clinically relevant drug interactions between anticancer drugs and psychotropic agents . Eur J Cancer Care (Engl) 2009 Dec 17 : Epub ahead of print

136.

Cheung YB, Goh C, Wee J, Khoo KS, Thumboo J (2009) Measurement properties of the Chinese language version of the functional assessment of cancer therapy-general in a Singaporean population . Ann Acad Med Singapore 38(3) : 38(3):225-229

137.

Ng DZ, Goh BK, Tham EH, Young SM, Ooi LL (2009) Cystic neoplasms of the pancreas: current diagnostic modalities and management . Ann Acad Med Singapore 38(3) : 251-259

138.

Koong HN, Khoo D, Higbee C, Travers M, Hyland A, Cummings KM, Dresler C (2009) Global air monitoring study: a multi-country comparison of levels of indoor air pollution in different workplaces . Ann Acad Med Singapore 38(3) : 202-206

139.

Madhavan K, Vathsala A, Ooi LL (2009) Organ and tissue transplantation . Ann Acad Med Singapore 38(4) : 289-292

140.

Gogna A, Lath N, Chang HM, Tan BS, Wong MC, Koh TH, Lim ST, Htoo MM, Lim WE (2009) Stent-assisted percutaneous angioplasty for extra-cranial carotid disease:experience at Singapore General Hospital . Ann Acad Med Singapore 38(9) : 756-762

141.

Beng AK, Fong CW, Shum E, Goh C, Goh KT, Chew SK (2009) Where the elderly die: the influence of socio-demographic factors and cause of death on people dying at home . Ann Acad Med Singapore 38(8) : 676-683

142.

Bisdas S, Foo CZ, Thng CH, Vogl TJ, Koh TS (2009) Optimization of Perfusion CT Protocol for Imaging of Extracranial Head and Neck Tumors . J Digit Imaging 22(5) : 437-448

143.

Lee SY, Pormento JG, Koong HN (2009) Abdominal paracentesis and thoracocentesis . Surg Laparosc Endosc Percutan Tech 19(2) : e32-e35.

144.

Huynh H, Fargnoli J (2009) Brivanib alaninate CYP17 Inhibitor, Oncolytic . Drugs Future 34(11) : 861-934

145.

Cheong LS, Lin F, Seah HS, Qian K, Zhao F, Thong PS, Soo KC, Olivo M, Kung SY (2009) Embedded Computing for Fluorescence Confocal Endomicroscopy Imaging . J Signal Process Syst 55(1-3) : 217-228

146.

Boussioutas A, Tan P (2009) Genomic and Proteomic Advances in Gastric Cancer . The Biology of Gastric Cancers Book Chapt 11 : 285-321

147.

Wang ML, Foo KF (2009) Adjuvant chemoradiotherapy for high-risk pancreatic cancer . Singapore Med J 50(1) : 43-48

148.

Toh CK (2009) The changing epidemiology of lung cancer . Methods Mol Biol 472 : 397-411

149.

Li GD, Luo R, Zhang J, Yeo KS, Xie F, Tan KWE, Caille D, Que J, Kon OL, Salto-Tellez M, Meda P, Lim SK (2009) Derivation of functional insulin-producing cell lines from primary mouse embryo culture . Stem Cell Res 2(1) : 29-40


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

150.

Li GD, Luo R, Zhang J, Yeo KS, Lian Q, Xie F, Tan EKW, Caille D, Kon OL, Salto-Tellez M, Meda P, Lim SK (2009) Generating mESC-derived insulin-producing cell lines through an intermediate lineage-restricted progenitor line . Stem Cell Res 2(1) : 41-55

151.

Chin WW, Thong PS, Bhuvaneswari R, Soo KC, Heng PW, Olivo M (2009) In-vivo optical detection of cancer using chlorin e6--polyvinylpyrrolidone induced fluorescence imaging and spectroscopy . BMC Med Imaging 9 : 1

152.

Law YM, Quek ST, Tan PH, Wong JS (2009) Adenoid cystic carcinoma of the breast . Singapore Med J 50(1) : e8-11

153.

Teo TH, Ho GH, Chaturverdi A, Khoo JB (2009) Tuberculosis of the chest wall: unusual presentation as a breast lump . Singapore Med J 50(3) : e97-e99

154.

Wang Z, Wang J, Chong SS, Lee CG (2009) Mining Potential Functional Polymorphisms at the ATP-Binding Cassette Transporter Family . Curr Pharmacogenomics Person Med 7(1) : 4058

155.

Chan A, Lim LL, Tao M (2009) Utilisation review of epoetin alfa in cancer patients at a cancer centre in Singapore . Singapore Med J 50(4) : 365-370

156.

Ching BC, Wong JS, Tan MH, Jara-Lazaro AR (2009) The many faces of intraosseous haemangioma: a diagnostic headache . Singapore Med J 50(5) : e195-e198

157.

Chew L, Shih V (2009) Cutaneous reaction associated with weekly docetaxel administration . J Oncol Pharm Pract 15(1) : 29-34

158.

Wong JS, Pang ALM (2009) Magnetic Resonance Imaging of Breast Tumors . Magnetic Resonance Spectroscopy of Breast Tumors. Nova Science Publishers, Inc. New York Chapt 4 : 6186

159.

Upile T, Jerjes W, Sterenborg HJ, El-Naggar AK, Sandison A, Witjes MJ, Biel MA, Bigio I, Wong BJ, Gillenwater A, Macrobert AJ, Robinson DJ, Betz CS, Stepp H, Bolotine L, McKenzie G, Mosse CA, Barr H, Chen Z, Berg K, D'Cruz AK, Stone N, Kendall C, Fisher S, Leunig A, Olivo M, RichardsKortum R, Soo KC, Bagnato V, Choo-Smith LP, Svanberg K, Tan IB, Wilson BC, Wolfsen H, Yodh AG, Hopper C (2009) Head & neck optical diagnostics: vision of the future of surgery . Head Neck Oncol 1(1) : 25

160.

Lim R, Tan PH, Cheng C, Agasthian T, Tan HL, Teh BT, Tan MH (2009) A unique case of spontaneous regression of metastatic papillary renal cell carcinoma: a case report . Cases J 2 : 7769

161.

Chan A, Leow CY, Hian SM (2009) Patients' perspectives and safe handling of oral anticancer drugs at an Asian cancer center . J Oncol Pharm Pract 15(3) : 161-165

162.

Rogers CG, Ditlev JA, Tan MH, Sugimura J, Qian CN, Cooper J, Lane B, Jewett MA, Kahnoski RJ, Kort EJ, Teh BT (2009) Microarray gene expression profiling using core biopsies of renal neoplasia . Am J Transl Res 1(1) : 55-61

163.

Wong TH, Tan YM (2009) Surgery for the palliation of intestinal obstruction in advanced abdominal malignancy . Singapore Med J 50(12) : 1139-1144

164.

De Silva DA, Woon FP, Lee MP, Chen CL, Chang HM, Wong MC (2009) Metabolic syndrome is associated with intracranial large artery disease among ethnic Chinese patients with stroke . J Stroke Cerebrovasc Dis 18(6) : 424-427 > 125


Highlighted Publications for 2010:

Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O'Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA Nature. 2010 Jan 21;463(7279):360-3. Abstract Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer. Inflammatory tumor microenvironment is associated with superior survival in hepatocellular carcinoma patients Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK, Lee KH, Abastado JP, Toh HC, Nardin A J Hepatol. 2010 Mar;52(3):370-9. Abstract Background & Aims: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. Methods: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). Results: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. Conclusions: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.

> 126


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells Tan SM, Li F, Rajendran P, Prem Kumar A, Hui KM, Sethi G J Pharmacol Exp Ther. 2010 Jul;334(1):285-93. Abstract The activation of signal transducer and activator of transcription 3 (STAT3) has been linked with the proliferation, survival, invasion, and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Agents that can suppress STAT3 activation have potential for the prevention and treatment of HCC. In this study, we tested an agent, beta-escin, for its ability to suppress STAT3 activation. We found that beta-escin, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janusactivated kinase 2. Vanadate treatment reversed the beta-escin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that beta-escin induced the expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation of constitutive STAT3 activation. beta-Escin also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, beta-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, these results suggest that beta-escin is a novel blocker of STAT3 activation that may have potential in the suppression of proliferation and chemosensitization in HCC. Global molecular dysfunctions in gastric cancer revealed by an integrated analysis of the phosphoproteome and transcriptome Guo T, Lee SS, Ng WH, Zhu Y, Gan CS, Zhu J, Wang H, Huang S, Sze SK, Kon OL Cell Mol Life Sci. 2010 Oct 16. Abstract We integrated LC-MS/MS-based and protein antibody array-based proteomics with genomics approaches to investigate the phosphoproteome and transcriptome of gastric cancer cell lines and endoscopic gastric biopsies from normal subjects and patients with benign gastritis or gastric cancer. More than 3,000 nonredundant phosphorylation sites in over 1,200 proteins were identified in gastric cancer cells. We correlated phosphoproteome data with transcriptome data sets and reported the expression of 41 protein kinases, 5 phosphatases and 65 phosphorylated mitochondrial proteins in gastric cancer cells. Transcriptional expression levels of 190 phosphorylated proteins were >2-fold higher in gastric cancer cells compared to normal stomach tissue. Pathway analysis demonstrated over-presentation of DNA damage response pathway and underscored critical roles of phosphorylated p53 in gastric cancer. This is the first study to comprehensively report the gastric cancer phosphoproteome. Integrative analysis of the phosphoproteome and transcriptome provided an expansive view of molecular signaling pathways in gastric cancer.

> 127


AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma Huynh H Cancer. 2010 Mar 1;116(5):1315-25. Abstract Background: The protein kinase B (AKT)/mammalian target of rapamycin (AKT/mTOR) and mitogen activated protein kinase/extracellular regulated kinase kinase/extracellular regulated kinase (MEK/ERK) signaling pathways have been shown to play an important role in hepatocellular carcinoma (HCC) growth and angiogenesis, suggesting that inhibition of these pathways may have therapeutic potential. Methods: We treated patient-derived HCC xenografts with 1) mTOR inhibitor rapamycin (RAPA); 2) MEK inhibitor AZD6244 (ARRY-142886); and 3) AZD6244 plus RAPA (AZD6244/RAPA). Western blotting was used to determine pharmacodynamic changes in biomarkers relevant to angiogenesis, mTOR pathway, and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. Results: We report here that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the antitumor and antiangiogenic activities of mTOR inhibitor RAPA in both orthotopic and ectopic models of HCC. Such inhibition led to increased apoptosis, decreased angiogenesis and cell proliferation, reduced expression of positive cell cycle regulators, and increase in proapoptotic protein Bim. Conclusions: Our findings indicate that the AZD6244/RAPA combination had antitumor and antiangiogenic effects in preclinical models of human HCC. Given the urgent need for effective therapies in HCC, clinical evaluating AZD6244/RAPA combination seems warranted.

> 128


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

1.

Wong NS, Buckman RA, Clemons M, Verma S, Dent S, Trudeau ME, Roche K, Ebos J, Kerbel R, Deboer GE, Sutherland DJ, Emmenegger U, Slingerland J, Gardner S, Pritchard KI (2010) Phase I/II Trial of Metronomic Chemotherapy With Daily Dalteparin and Cyclophosphamide, TwiceWeekly Methotrexate, and Daily Prednisone As Therapy for Metastatic Breast Cancer Using Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor Levels As Markers of Response . J Clin Oncol 28(5) : 723-730

2.

Tan DS, Ng QS, Tan IB, Lim ST, Lim WT (2010) Truth About ERCC1 in Lung Cancer . J Clin Oncol 28(10) : e162

3.

Tan MH, Leo NQ, Loy EY, Lim WY, Chia KS (2010) Association Between Being Underweight and Outcomes in Breast Cancer: Alternative Explanations . J Clin Oncol 28(11) : e177

4.

Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY (2010) Phase III Trial Comparing Vinflunine With Docetaxel in Second-Line Advanced Non-Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy . J Clin Oncol 28(13) : 2167-2173

5.

Furge KA, Mackeigan JP, Teh BT (2010) Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new . Lancet Oncol 11(6) : 571-578

6.

Gough DJ, Messina NL, Hii L, Gould JA, Sabapathy K, Robertson AP, Trapani JA, Levy DE, Hertzog PJ, Clarke CJ, Johnstone RW (2010) Functional crosstalk between type I and II interferon through the regulated expression of STAT1 . PLoS Biol 8(4) : e1000361

7.

Dulloo I, Gopalan G, Melino G, Sabapathy K (2010) The antiapoptotic DeltaNp73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway . Proc Natl Acad Sci USA 107(11) : 4902-4907

8.

Cheung CC, Yang C, Berger T, Zaugg K, Reilly P, Elia AJ, Wakeham A, You-Ten A, Chang N, Li L, Wan Q, Mak TW (2010) Identification of BERP (brain-expressed RING finger protein) as a p53 target gene that modulates seizure susceptibility through interacting with GABAA receptors . Proc Natl Acad Sci USA 107(26) : 11883-11888

9.

McIlwain DR, Pan Q, Reilly P, Elia AJ, McCracken S, Wakeham AC, Itie-Youten A, Blencowe BJ, Mak TW (2010) Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay . Proc Natl Acad Sci USA 107(27) : 12186-12191

10.

Guo T, Zhu Y, Gan CS, Lee SS, Zhu J, Wang H, Li X, Christensen J, Huang S, Kon OL, Sze SK (2010) Quantitative proteomics discloses MET expression in mitochondria as a direct target of MET kinase inhibitor in cancer cells . Mol Cell Proteomics 2010 Aug 16 : Epub ahead of print

11.

Toh WH, Nam SY, Sabapathy K (2010) An essential role for p73 in regulating mitotic cell death . Cell Death Differ 17(5) : 787-800

12.

Lee MK, Tong WM, Wang ZQ, Sabapathy K (2010) Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo . Cell Death Differ 2010 Jul 30 : Epub ahead of print

13.

Fan HM, Olivo M, Shuter B, Yi JB, Bhuvaneswari R, Tan HR, Xing GC, Ng CT, Liu L, Lucky SS, Bay BH, Ding J (2010) Quantum Dot Capped Magnetite Nanorings as High Performance Nanoprobe for Multiphoton Fluorescence and Magnetic Resonance Imaging . J Am Chem Soc 132(42) : 14803-14811 > 129


> 130

14.

Wang Y, Lu Y, Toh ST, Sung WK, Tan P, Chow P, Chung AY, Jooi LL, Lee CG (2010) Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3 . J Hepatol 53(1) : 57-66

15.

Huang D, Ding Y, Li Y, Luo WM, Zhang ZF, Snider J, VandenBeldt K, Qian CN, Teh BT (2010) Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma . Cancer Res 70(3) : 1053-1062

16.

Ranganath SH, Fu Y, Arifin DY, Kee I, Zheng L, Lee HS, Chow PK, Wang CH (2010) The use of submicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice . Biomaterials 31(19) : 51995207

17.

Wang J, Ronaghi M, Chong SS, Lee CG (2010) pfSNP: An integrated potentially functional SNP resource that facilitates hypotheses generation through knowledge syntheses . Hum Mutat 2010 Jul 29 : Epub ahead of print

18.

Ong SJ, Teo M, Lim KH, Choo SP, Toh HC (2010) Rapamycin and Thalidomide Treatment of a Patient with Refractory Metastatic Gastroesophageal Adenocarcinoma: A Case Report . Oncologist 15(9) : 965-968

19.

Chia WK, Wang WW, Lim WT, Tai WM, Sun L, Thng CH, Soe Y, Yap SP, Tan EH, Toh HC (2010) Nonmyeloablative Allogeneic Stem Cell Transplantation for Nasopharyngeal Carcinoma . Oncologist 2010 Oct 27 : Epub ahead of print

20.

Low SY, Takano AM, Devanand A, Ngeow JY (2010) Recurring mouth ulcer and skin rash in a man with abnormal chest radiograph . Chest 137(4) : 983-988

21.

Jaichandran S, Krishnan S, Ng WH, Lee SS, Phan TT, Kon OL (2010) Biosafety assessment of site-directed transgene integration in human umbilical cord-lining cells . Mol Ther 18(7) : 1346-1356

22.

Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2010) Author's reply to comment on "The effect of photodynamic therapy on tumor angiogenesis. Cellular and Molecular Life Sciences, 66, 2275-2283" . Cell Mol Life Sci 67(9) : 1561

23.

Ang MK, Ooi AS, Thike AA, Tan P, Zhang Z, Dykema K, Furge K, Teh BT, Tan PH (2010) Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression . Breast Cancer Res Treat 2010 Oct 14 : Epub ahead of print

24.

Lim WT, Tan EH, Toh CK, Hee SW, Leong SS, Ang PC, Wong NS, Chowbay B (2010) Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol-PM) in patients with solid tumors . Ann Oncol 21(2) : 382-388

25.

Tan EH, Ramlau R, Pluzanska A, Kuo HP, Reck M, Milanowski J, Au JS, Felip E, Yang PC, Damyanov D, Orlov S, Akimov M, Delmar P, Essioux L, Hillenbach C, Klughammer B, McLoughlin P, Baselga J (2010) A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer . Ann Oncol 21(2) : 217-222

26.

Ngeow J, Lim WT, Leong SS, Ang MK, Toh CK, Gao F, Chowbay B, Tan EH (2010) Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma . Ann Oncol 2010 Aug 17 : Epub ahead of print


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

27.

Cho SJ, Ahn YH, Maiti KK, Dinish US, Fu CY, Thoniyot P, Olivo M, Chang YT (2010) Combinatorial synthesis of a triphenylmethine library and their application in the development of surface enhanced Raman scattering (SERS) probes . Chem Commun (Camb) 46(5) : 722-724

28.

Tan SJ, Lakshmi RL, Chen P, Lim WT, Yobas L, Lim CT (2010) Versatile label free biochip for the detection of circulating tumor cells from peripheral blood in cancer patients . Biosens Bioelectron 2010 Jul 22 : Epub ahead of print

29.

Maiti KK, Dinish US, Fu CY, Lee JJ, Soh KS, Yun SW, Bhuvaneswari R, Olivo M, Chang YT (2010) Development of biocompatible SERS nanotag with increased stability by chemisorption of reporter molecule for in vivo cancer detection . Biosens Bioelectron 26(2) : 398-403

30.

Dinish US, Yaw FC, Agarwal A, Olivo M (2010) Development of highly reproducible nanogap SERS substrates: Comparative performance analysis and its application for glucose sensing . Biosens Bioelectron 2010 Sep 23 : Epub ahead of print

31.

Koo YX, Tan DS, Tan IB, Tao M, Chow WC, Lim ST (2010) Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy . Cancer 116(1) : 115-121

32.

Tan IB, Ang KK, Ching BC, Mohan C, Toh CK, Tan MH (2010) Testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults: a meta-analysis and systematic review . Cancer 116(19) : 4520-4532

33.

Song JY, Han HS, Sabapathy K, Lee BM, Yu E, Choi J (2010) Expression of a homeostatic regulator, Wip1 (wild-type p53-induced phosphatase), is temporally induced by c-Jun and p53 in response to UV irradiation . J Biol Chem 285 : 9067-9076

34.

Ngeow JY, Leong SS, Gao F, Toh CK, Lim WT, Tan EH, Poon D (2010) Impact of comorbidities on clinical outcomes in non-small cell lung cancer patients who are elderly and/or have poor performance status . Crit Rev Oncol Hematol 76(1) : 53-60

35.

Ho IA, Miao L, Sia KC, Wang GY, Hui KM, Lam PY (2010) Targeting human glioma cells using HSV-1 amplicon peptide display vector . Gene Ther 17(2) : 250-260

36.

Chen NK, Tan SY, Udolph G, Kon OL (2010) Insulin expressed from endogenously active glucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetes therapy . Gene Ther 17(5) : 592-605

37.

Gao F, Wee J, Wong HB, Machin D (2010) Quality-of-Life-Adjusted Survival Analysis of Concurrent Chemo Radiotherapy for Locally Advanced (Nonmetastatic) Nasopharyngeal Cancer . Int J Radiat Oncol Biol Phys 78(2) : 454-460

38.

Mirzayans R, Andrais B, Scott A, Paterson MC, Murray D (2010) Single-cell analysis of p16(INK4a) and p21(WAF1) expression suggests distinct mechanisms of senescence in normal human and Li-Fraumeni Syndrome fibroblasts . J Cell Physiol 223(1) : 57-67

39.

Toh CK, Ahmad B, Soong R, Chuah KL, Tan SH, Hee SW, Leong SS, Tan EH, Lim WT (2010) Correlation between Epidermal Growth Factor Receptor Mutations and Expression of Female Hormone Receptors in East-Asian Lung Adenocarcinomas . J Thorac Oncol 5(1) : 17-22

40.

Seet RC, Kasiman K, Gruber J, Tang SY, Wong MC, Chang HM, Chan YH, Halliwell B, Chen CP (2010) Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study . Atherosclerosis 209(1) : 215-219 > 131


> 132

41.

Khoo D, Chiam Y, Ng P, Berrick AJ, Koong HN (2010) Phasing-out tobacco: proposal to deny access to tobacco for those born from 2000 . Tob Control 19(5) : 355-360

42.

Bai J, Sadrolodabaee L, Ching CB, Chowbay B, Chen WN (2010) A Comparative Proteomic Analysis of HepG2 cells Incubated by S(-) and R(+) Enantiomers of Anti-coagulating Drug Warfarin . Proteomics 10(7) : 1463-1473

43.

Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, Chen PJ, Lin ZZ, Chao TY, Cheng AL (2010) Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma . Br J Cancer 102(6) : 981-986

44.

Hahn MA, Howell VM, Gill AJ, Clarkson A, Weaire-Buchanan G, Robinson BG, Delbridge L, Gimm O, Schmitt WD, Teh BT, Marsh DJ (2010) CDC73/HRPT2 CpG island hypermethylation and mutation of 5'-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors . Endocr Relat Cancer 17(1) : 273-282

45.

Huynh H (2010) Molecularly targeted therapy in hepatocellular carcinoma . Biochem Pharmacol 80(5) : 550-560

46.

Ong DC, Yam WC, Siu GK, Lee AS (2010) Rapid Detection of Rifampicin- and IsoniazidResistant Mycobacterium tuberculosis by High-Resolution Melting Analysis . J Clin Microbiol 48(4) : 1047-1054

47.

Ho IA, Ng WH, Lam PY (2010) FasL and FADD delivery by a glioma-specific and cell cycledependent HSV-1 amplicon virus enhanced apoptosis in primary human brain tumors . Mol Cancer 9(1) : 270

48.

Tan DS, Gerlinger M, Teh BT, Swanton C (2010) Anti-cancer drug resistance: understanding the mechanisms through the use of integrative genomics and functional RNA interference . Eur J Cancer 46(12) : 2166-2177

49.

Xie M, Sabapathy K (2010) Tyrosine 170 is dispensable for c-Jun turnover . Cell Signal 22(2) : 330-337

50.

Thike AA, Iqbal J, Cheok PY, Chong AP, Tse GM, Tan B, Tan P, Wong NS, Tan PH (2010) Triple Negative Breast Cancer: Outcome Correlation With Immunohistochemical Detection of Basal Markers . Am J Surg Pathol 34(7) : 956-964

51.

Sun YJ, Luo JT, Wong SY, Lee AS (2010) Analysis of rpsL and rrs mutations in Beijing and non-Beijing streptomycin-resistant Mycobacterium tuberculosis isolates from Singapore . Clin Microbiol Infect 16(3) : 287-289

52.

Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, Tan T, Chua DT, O'Sullivan B, Tung R, Ng WT, Leung TW, Leung SF, Yau S, Zhao C, Tan EH, Au GK, Siu L, Fung KK, Lau WH (2010) A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma . Radiother Oncol 2010 Oct 22 : Epub ahead of print

53.

Lal S, Mahajan A, Chen WN, Chowbay B (2010) Pharmacogenetics of Target Genes Across Doxorubicin Disposition Pathway: A Review . Curr Drug Metab 11(1) : 115-128

54.

Ngeow JY, Toh CK (2010) The Role of Pemetrexed Combined with Gemcitabine for NonSmall-Cell Lung Cancer . Curr Drug Targets 11(1) : 61-66


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

55.

Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G (2010) Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells . Cancer Lett 292(2) : 197-207

56.

Subramaniam K, Ooi LL, Hui KM (2010) Transcriptional down-regulation of IGFBP-3 in human hepatocellular carcinoma cells is mediated by the binding of TIA-1 to its AT-rich element in the 3'-untranslated region . Cancer Lett 297(2) : 259-268

57.

Koh TS, Thng CH, Hartono S, Kwek JW, Khoo JB, Miyazaki K, Collins DJ, Orton MR, Leach MO, Lewington V, Koh DM (2010) Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model . Magn Reson Med 2010 Sep 21 : Epub ahead of print

58.

Toh HC, Chia WK, Sun L, Thng CH, Soe Y, Phoon YP, Yap SP, Lim WT, Tai WM, Hee SW, Tan SH, Leong SS, Tan EH (2010) Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation . Bone Marrow Transplant 2010 Jul 26 : Epub ahead of print

59.

Bisdas S, Rumboldt Z, Surlan-Popovic K, Baghi M, Koh TS, Vogl TJ, Mack MG (2010) Perfusion CT in squamous cell carcinoma of the upper aerodigestive tract: long-term predictive value of baseline perfusion CT measurements . Am J Neuroradiol 31(3) : 576-581

60.

Surlan-Popovic K, Bisdas S, Rumboldt Z, Koh TS, Strojan P (2010) Changes in perfusion CT of advanced squamous cell carcinoma of the head and neck treated during the course of concomitant chemoradiotherapy . Am J Neuroradiol 31(3) : 570-575

61.

Farber LJ, Kort EJ, Wang P, Chen J, Teh BT (2010) The tumor suppressor parafibromin is required for posttranscriptional processing of histone mRNA . Mol Carcinog 49(3) : 215-223

62.

Chin WW, Praveen T, Heng PW, Olivo M (2010) Effect of polyvinylpyrrolidone on the interaction of chlorin e6 with plasma proteins and its subcellular localization . Eur J Pharm Biopharm 76(2) : 245-252

63.

Sia KC, Chong WK, Ho IA, Yulyana Y, Endaya B, Huynh H, Lam PY (2010) Hybrid herpes simplex virus/Epstein-Barr virus amplicon viral vectors confer enhanced transgene expression in primary human tumors and human bone marrow-derived mesenchymal stem cells . J Gene Med 12(10) : 848-858

64.

Leong SS, Fong KW, Lim WT, Toh CK, Yap SP, Hee SW, Tan EH (2010) A phase II trial of induction gemcitabine and vinorelbine followed by concurrent vinorelbine and radiotherapy in locally advanced non-small cell lung cancer . Lung Cancer 67(3) : 325-329

65.

Ng QS, Goh V, Milner J, Sundin J, Wellsted D, Saunders MI, Hoskin PJ (2010) Quantitative helical dynamic contrast enhanced computed tomography assessment of the spatial variation in whole tumour blood volume with radiotherapy in lung cancer . Lung Cancer 69(1) : 71-76

66.

Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST (2010) Prognostic impact of bleomycin-induced pneumonitis on the outcome of Hodgkin's lymphoma . Ann Hematol 2010 Jul 31 : Epub ahead of print

67.

Chua HW, Ng D, Choo S, Lum SS, Li H, Soh LY, Sabapathy K, Seow A (2010) Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among nonsmoking Chinese women in Singapore . BMC Cancer 10(1) : 88

> 133


> 134

68.

Tan MH, Wong CF, Tan HL, Yang XJ, Ditlev J, Matsuda D, Khoo SK, Sugimura J, Fujioka T, Furge KA, Kort E, Giraud S, Ferlicot S, Vielh P, Amsellem-Ouazana D, Debre B, Flam T, Thiounn N, Zerbib M, Benoit G, Droupy S, Molinie V, Vieillefond A, Tan PH, Richard S, Teh BT (2010) Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma . BMC Cancer 10(1) : 196

69.

Ho IA, Hui KM, Lam PY (2010) Isolation of peptide ligands that interact specifically with human glioma cells . Peptides 31(4) : 644-650

70.

Lim JS, Singh O, Ramasamy RD, Ramasamy S, Subramanian K, Lee EJ, Chowbay B (2010) Pharmacogenetics of CYP1A2, novel polymorphisms and haplotypes in three distinct Asian populations . Drug Metab Pharmacokinet 2010 Oct 1 : Epub ahead of print

71.

Olivo M, Lucky SS, Kent Mancer JF, Lau WK (2010) Altered expression of cell adhesion molecules leads to differential uptake of hypericin in urothelial cancer . Urol Oncol 2010 Oct 6 : Epub ahead of print

72.

Bhuvaneswari R, Thong PS, Gan YY, Soo KC, Olivo M (2010) Evaluation of hypericin-mediated photodynamic therapy in combination with angiogenesis inhibitor bevacizumab using in vivo fluorescence confocal endomicroscopy . J Biomed Opt 15(1) : 011114

73.

Vasudevan S, Chen GC, Andika M, Agarwal S, Chen P, Olivo M (2010) Dynamic quantitative photothermal monitoring of cell death of individual human red blood cells upon glucose depletion . J Biomed Opt 15(5) : 057001

74.

Ang MK, Tan SB, Lim WT (2010) Phase II clinical trials in oncology: are we hitting the target . Expert Rev Anticancer Ther 10(3) : 427-438

75.

Idirisinghe PK, Thike AA, Cheok PY, Tse GM, Lui PC, Fook-Chong S, Wong NS, Tan PH (2010) Hormone Receptor and c-ERBB2 Status in Distant Metastatic and Locally Recurrent Breast Cancer: Pathologic Correlations and Clinical Significance . Am J Clin Pathol 133(3) : 416429

76.

Yap KY, Kuo EY, Lee JJ, Chui WK, Chan A (2010) An onco-informatics database for anticancer drug interactions with complementary and alternative medicines used in cancer treatment and supportive care: an overview of the OncoRx project . Support Care Cancer 18(7) : 883891

77.

Chan A, Fu WH, Shih V, Coyuco JC, Tan SH, Ng R (2010) Impact of colony-stimulating factors to reduce febrile neutropenic events in breast cancer patients receiving docetaxel plus cyclophosphamide chemotherapy . Support Care Cancer 2010 Mar 17 : Epub ahead of print

78.

Chan A, Tan EH (2010) How well does the MESTT correlate with CTCAE scale for the grading of dermatological toxicities associated with oral tyrosine kinase inhibitors? . Support Care Cancer 2010 Sep 5 : Epub ahead of print

79.

Huynh H (2010) Tyrosine kinase inhibitors to treat liver cancer . Expert Opin Emerg Drugs 15(1) : 13-26

80.

Glenn ST, Head KL, Teh BT, Gross KW, Kim HL (2010) Maximizing RNA yield from archival renal tumors and optimizing gene expression analysis . J Biomol Screen 15(1) : 80-85


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

81.

Tan MH, Kanesvaran R, Li H, Tan LH, Tan PH, Wong FC, Chia SK, Teh BT, Yuen J, Chong TW (2010) Comparison of the UCLA Integrated Staging System and the Leibovich score in survival prediction for patients with nonmetastatic clear cell renal cell carcinoma . Urology 75(6) : 1365-1370; 1370.e1-e3

82.

Narasimhalu K, Effendy S, Sim CH, Lee JM, Chen I, Hia SB, Xue HL, Corrales MP, Chang HM, Wong MC, Chen CP, Tan EK (2010) A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease . Acta Neurol Scand 121(4) : 217-224

83.

Iyer NG, Clark JR, Singham S, Zhu J (2010) Role of pretreatment 18FDG-PET/CT in surgical decision-making for head and neck cancers . Head Neck 32(9) : 1202-1208

84.

Tan HK, Giger R, Auperin A, Bourhis J, Janot F, Temam S (2010) Salvage surgery after concomitant chemoradiation in head and neck squamous cell carcinomas-Stratification for postsalvage survival . Head Neck 32(2) : 139-147

85.

Leong C, Ngeow JY, Tan IB, Quek R, Tao M, Loh Y, Tan HC, Lim ST (2010) Second hematologic malignancies after ABVD: Two case reports and a retrospective study of 183 Hodgkin lymphoma patients . Acta Oncol 49(2) : 257-259

86.

Chay WY, Chew L, Yeoh TT, Tan MH (2010) An association between transient hypokalemia and severe acute oxaliplatin-related toxicity predominantly in women . Acta Oncol 49(4) : 515-517

87.

Yap KY, Ho YX, Chui WK, Chan A (2010) Harnessing the internet cloud for managing drug interactions with chemotherapy regimens in patients with cancer suffering from depression . Acta Oncol 49(8) : 1235-1245

88.

Lai GG, Koo YX, Tao M, Tan TT, Lim ST (2010) Use of rituximab in combination with highdose methotrexate in the treatment of primary central nervous system lymphoma in a mycophenolate mofetil treated patient with lupus nephritis . Acta Oncol 2010 Jul 29 : Epub ahead of print

89.

Yap KY, Chan A, Chui WK, Chen YZ (2010) Cancer informatics for the clinician: An interaction database for chemotherapy regimens and antiepileptic drugs . Seizure 19(1) : 59-67

90.

Tham IW, Lin S, Pan J, Han L, Lu JJ, Wee J (2010) Intensity-Modulated Radiation Therapy Without Concurrent Chemotherapy for Stage IIB Nasopharyngeal Cancer . Am J Clin Oncol 33(3) : 294-299

91.

Chua TC, Liauw W, Koong HN, Esquivel J (2010) Surgical Therapies in Metastatic Colorectal Cancer With a Potential for Cure . Am J Clin Oncol 2010 May 21 : Epub ahead of print

92.

Teh J, Yap SP, Tham IW, Sethi VK, Chua EJ, Yeo R, Ho TH, Tay EH, Chia YN, Soh LT, Khoo-Tan HS (2010) Concurrent chemoradiotherapy incorporating high-dose rate brachytherapy for locally advanced cervical carcinoma: survival outcomes, patterns of failure, and prognostic factors . Int J Gynecol Cancer 20(3) : 428-433

93.

Kumar VJ, Nin CY, Kuei LY, Tan KH, Yeo R, Lam PY (2010) Survival and disease relapse in surgical stage I endometrioid adenocarcinoma of the uterus after adjuvant vaginal vault brachytherapy . Int J Gynecol Cancer 20(4) : 564-569

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> 136

94.

Cheung YB, Xu Y, Tan SH, Cutts F, Milligan P (2010) Estimation of intervention effects using first or multiple episodes in clinical trials: The Andersen-Gill model re-examined . Stat Med 29(3) : 328-336

95.

Chan A, Yap KY (2010) Detection and management of oncology drug interactions: Can we do better? . Maturitas 65(3) : 181-182

96.

Thng CH, Koh TS, Collins DJ, Koh DM (2010) Perfusion magnetic resonance imaging of the liver . World J Gastroenterol 16(13) : 1598-1609

97.

Tham CK, Choo SP, Poon D, Toh HC, Ong SY, Tan SH, Wang ML, Foo KF (2010) Capecitabine with radiation is an effective adjuvant therapy in gastric cancers . World J Gastroenterol 16(29) : 3709-3715

98.

Cheung YB, Wee HL, Thumboo J, Goh C, Pietrobon R, Toh HC, Yong YF, Tan SB (2010) Risk communication in clinical trials: A cognitive experiment and a survey . BMC Med Inform Decis Mak 10 : 55

99.

Ang D, Teo EK, Ang TL, Lim KH, Madhukumar P, Chung AY, Wang Y, Fock KM (2010) Unexplained Small-Bowel Obstruction in a Patient with Presumptive Achalasia: Need for Early Recognition of Chronic Intestinal Pseudo-obstruction (CIPO) . Dig Dis Sci 55(9) : 2691-2692

100.

Linn YC, Hui KM (2010) Cytokine-induced NK-like T cells: from bench to bedside . J Biomed Biotechnol 2010 : 435745

101.

Hao Q, Chang HM, Wong MC, Wong KS, Chen C (2010) Frequency of Microemboli Signal in Stroke Patients Treated with Low Molecular Weight Heparin or Aspirin . J Neuroimaging 20(2) : 118-121

102.

Yap KY, Raaj S, Chan A (2010) OncoRx-IQ: a tool for quality assessment of online anticancer drug interactions . Int J Qual Health Care 22(2) : 93-106

103.

Cheung YT, Yap KY, Chui WK, Chan A (2010) Drug-Drug Interactions between Oral Antiepileptics and Oral Anticancer Drugs: Implications to Clinicians . Eur Neurol 64(2) : 88-94

104.

Chua TC, Koong HN (2010) Curative pulmonary metastasectomy for non-seminomatous germ cell tumor of the testis . ANZ J Surg 80(5) : 380-381

105.

Mohd Omar MF, Huang N, Ou K, Yu K, Putti TC, Jikuya H, Ichikawa T, Nishimura O, Tan P, SaltoTellez M (2010) Molecular-assisted immunohistochemical optimization . Acta Histochem 112(6) : 519-528

106.

Chiang J, Chan A, Shih V, Hee SW, Tao M, Lim ST (2010) A prospective study to evaluate the feasibility and economic benefits of rapid infusion rituximab at an Asian cancer center . Int J Hematol 91(5) : 826-830

107.

Iyer NG, Shaha AR, Silver CE, Devaney KO, Rinaldo A, Pellitteri PK, Ferlito A (2010) Thyroid incidentalomas: to treat or not to treat . Eur Arch Otorhinolaryngol 267(7) : 1019-26

108.

Tan MH, Yang J, Tan HL, Wong CF, Tan PH, Sim HG, Ang P, Toh CK, Tay MH, Poon E, Ooi AS, Teh BT (2010) A Unique Pair of Monozygotic Twins with Concordant Clear Cell Renal Cell Carcinoma: A Case Report . Ann Acad Med Singapore 39(1) : 61-63


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

109.

Teo MC (2010) Peritoneal-based malignancies and their treatment . Ann Acad Med Singapore 39(1) : 54-57

110.

Chan JJ, Loh AH, Sim HG, Tan MH, Toh CK (2010) Coexistence of unicentric Castleman's Disease and locally advanced papillary renal cell carcinoma: More than a coincidental association? . Ann Acad Med Singapore 39(7) : 584-592

111.

Kanesvaran R, Phipps C, Cheng CW, Chan MM, Khoo D, Tan MH (2010) Management of thrombotic thrombocytopenic purpura in metastatic prostate cancer with only endocrine therapy . Ann Acad Med Singapore 39(7) : 580-582

112.

Tan MH, Chay WY, Ng JH, Teh BT, Chew L (2010) Transient bilateral abducens neuropathy with post-tetanic facilitation and acute hypokalemia associated with oxaliplatin: a case report . J Med Case Reports 4 : 36

113.

Quek R, George S (2010) Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib . Biologics 4 : 19-31

114.

Chen LH, Ho H, Lazaro R, Thng CH, Yuen J, Ng WS, Cheng C (2010) Optimum slicing of radical prostatectomy specimens for correlation between histopathology and medical images . Int J Comput Assist Radiol Surg 5(5) : 471-487

115.

Yang Y, Kort EJ, Ebrahimi N, Zhang Z, Teh BT (2010) Dual KS: Defining Gene Sets with Tissue Set Enrichment Analysis . Cancer Inform 9 : 1-9

116.

Wee J, Ha TC, Loong SL, Qian CN (2010) Is Nasopharyngeal Cancer really a "Cantonese Cancer"? . Chinese J Cancer 29(5) : 517-526

117.

Iyer NG, Shaha AR (2010) Complications of thyroid surgery: prevention and management . Minerva Chir 65(1) : 71-82

118.

Lee HP, Chew CT, Consigliere DT, Heng D, Huang DT, Khoo J, Khoo KS, Low J, Lui S, Ooi LL, Puvanendran R, Siow A, Tan A, Yeoh KG (2010) Ministry of health clinical practice guidelines: cancer screening . Singapore Med J 51(2) : 170-175

119.

Thng CH, Hartono S, Koh TS, Koh DM (2010) An Introduction to MR Perfusion Imaging of the Liver . Proceedings of Singapore Healthcare 19(1) : 26-35

120.

Eng AKH, Kon OL (2010) Molecular Genetics of Gastric Adenocarcinoma . Proceedings of Singapore Healthcare 19(1) : 57-63

121.

Tan SB (2010) Three Myths about Biostatisticians . Proceedings of Singapore Healthcare 19(1) : 83

122.

Agasthian T, Lin SJ (2010) Clinical outcome of video-assisted thymectomy for myasthenia gravis . Asian Cardiovasc Thorac Ann 18(3) : 234-239

123.

Li Y, Zhang ZF, Chen J, Huang D, Ding Y, Tan MH, Qian CN, Resau JH, Kim H, Teh BT (2010) VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor and endothelial cells in clear cell renal cell carcinoma . Am J Transl Res 2(3) : 296-308

124.

Chan Q, Chan A (2010) Impact of erythropoiesis-stimulating agent prescribing at an Asian cancer center, after release of safety advisories . J Oncol Pharm Pract 2010 Jul 21. [ : Epub ahead of print > 137


> 138

125.

Agasthian T (2010) Revisiting the prone position in video-assisted thoracoscopic surgery . Asian Cardiovasc Thorac Ann 18(4) : 364-367

126.

Tai D, Poon D (2010) Molecular and other novel advances in treatment of metastatic epithelial and medullary thyroid cancers . J Oncol 2010 (2010) : 398564

127.

Tan PW, Wong CH, Koong HN, Tan BK (2010) Chest wall reconstruction using a combined musculocutaneous anterolateral-anteromedial thigh flap . Indian J Plast Surg 43(1) : 88-91

128.

Reilly PT, Afzal S, Wakeham A, Haight J, You-Ten A, Zaugg K, Dembowy J, Young A, Mak TW (2010) Generation and characterization of the anp32e-deficient mouse. . PLoS ONE 5(10) : e13597

129.

Tan G, Teo M, Choo SP (2010) Hypoglycaemia in a 63-Year-Old Female with a Large, Recurrent, Metastatic Gastrointestinal Stromal Tumour (GIST) . J Gastrointest Cancer 2010 Nov 6 : Epub ahead of print


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

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Humphrey Oei Distinguished Lecture Series


DISTINGUISHED LECTURE SERIES

The NCCS Humphrey Oei Distinguished Lecture Series aspires to be one of Singapore’s leading forums for intellectual inquiry and discussion in cancer and biological research. With eminent scientists as guest speakers, the series hopes to create an environment for exploration of ideas and advances in cancer biology and medicine.

The Origins of Pandemic Influenza 19 April 2007

Distinguished Speaker Sir John Skehel Honorary Professor, Department of Virology, University College London Board Member, National Biological Standards Board, UK

As one of the world’s leading virologists, Sir John Skehel has made a very special contribution to medical science. His work elucidates the pathogenicity and immunogenicity of influenza viruses through studies on the molecular and structural interactions of the haemagglutinin membrane glycoproteins and its host cell receptors. Because of his research, the medical community has a better understanding of the pandemic influenza virus outbreak in 1918 that claimed more than 20 million lives, and it has provided new insights into the pandemic potential of the H5N1 influenza viruses. Sir John earned his PhD from the University of Manchester in 1966, and served as Director of the National Institute for Medical Research in 1969. He was conferred Fellow of the Royal Society in 1984. Two years later he was awarded the Wilhelm Feldberg Prize, and in June 1996 he was knighted. Sir John won the Royal Society’s Royal Medal in 2003. He is an Honorary Professor at the University College London, Department of Virology. Sir John was also appointed a board member of National Biological Standards Board (NBSB), which has a key role in advising the British government on public health threats like the bird flu.

SINGLE NUCLEOTIDE POLYMORPHISMS IN THE P53 PATHWAY: CANCER, GENDER AND FECUNDITY 12 November 2007

Distinguished Speaker Prof Arnold Levine Professor, The Simons Center for Systems Biology, Institute for Advanced Study, Princeton Joint Professor, Pediatrics and Biochemistry Departments, Cancer Institute of New Jersey > 142

Prof Arnold Levine has made significant contributions in the field of oncology in his research on the causes of cancer in both humans and animals. He was the first to discover the p53 tumour suppressor gene, which acts to protect individuals from developing cancer. Following his discovery, thousands of researchers have followed in Prof Levine’s footsteps, seeking to focus on the p53 gene, which is the most commonly mutated gene in cancer. Prof Levine is currently a Professor at The Simons Center for Systems Biology at the Institute for Advanced Study in Princeton and a joint professor in the Paediatrics and Biochemistry Departments at the Cancer Institute of New Jersey. He received his PhD in microbiology from the University of Pennsylvania School of Medicine. Later he was a post-doctoral fellow of the Public Health Service at the California Institute of Technology. He has received many honours, the most recent include the Medal for Outstanding Contributions to Biomedical Research from Memorial Sloan-Kettering Cancer Center (2000), the Albany Medical Center Prize in Medicine and Biomedical Research (2001), Award for Basic Research from the Surgical Society of Oncologists (2003) and the Bristol Myers Squibb Freedom to Discover Award (2005).


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

DID THE ONCOGENE REVOLUTION SETBACK CLINICAL ONCOLOGY? 17 July 2008

Distinguished Speaker Prof Tak Wah Mak Director, Campbell Family Institute for Breast Cancer Research, Prince Margaret Hospital University Professor, University of Toronto

Prof Tak W. Mak is the Director of the Campbell Family Institute for Breast Cancer Research in the Princess Margaret Hospital and a University Professor at University of Toronto. He was trained at the University of Wisconsin in Madison, University of Alberta and Ontario Cancer Institute. Prof Mak’s research interests centre on immune recognition and regulation, cell survival and cell death in normal and malignant cells. He is best known as the leading scientist of the group that first cloned the genes of the human T-cell antigen receptor. His recent works include the creation of a series of genetically altered mice that have proved critical to unravelling intracellular programmes governing the development and function of the immune system, and the dissection of signal transduction cascades in various cell survival and apoptotic pathways. Prof Mak is an Officer of the Order of Canada and has been elected Foreign Associate of the National Academy of Sciences (USA), Foreign Associate of the American Academy of Arts and Sciences, as well as Fellow of the Royal Society of London (UK). He has won international recognition in the forms of the Emil von Behring Prize, King Faisal Prize for Medicine, Gairdner Foundation International Award, Sloan Prize of the General Motors Cancer Foundation, Novartis Prize in Immunology and Paul Ehrlich Prize of Germany.

PALLIATIVE CARE AS A HUMAN RIGHT 14 October 2008

Distinguished Speaker Dr Richard Payne Professor of Medicine and Divinity and Esther Colliflower Director, Institute on Care at the End of Life, Duke University Divinity School

Dr Richard Payne is a leading expert on pain relief and caring for those with advanced disease in the fields of oncology and neurology. He is Professor of Medicine and Divinity and the Esther Colliflower Director of the Institute on Care at the End of Life in the Duke University’s Divinity School. A graduate of Yale University and Harvard University, Dr Payne completed his post-graduate fellowship in neuro-oncology and pain medicine at Memorial Sloan-Kettering Cancer Center (MSKCC), New York. Dr Payne has served on numerous panels and advisory committees, including the editorial boards of the journal, Pain, the Journal of Pain and Symptom Management, the official journals of the American Pain Society and the National Hospice and Palliative Care Organization (NHPCO), respectively. Currently Dr Payne is Chair of the Board of Directors of the Foundation for Hospices in Sub-Saharan Africa (FHSSA), an affiliate of the NHPCO; and sits on the boards of directors of the National Coalition of Cancer Survivors and the Hastings Bioethics Center. For his work and dedication, Dr Payne received a Distinguished Service Award from the American Pain Society; Urban Resources Institute’s Humanitarian Award, and the Janssen Excellence in Pain Award.

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INFECTIOUS CAUSES OF HUMAN CANCERS: PERSPECTIVES 2 April 2009

Distinguished Speaker Prof Harald zur Hausen Professor Emeritus

Prof Harald zur Hausen, best known for his work in virus-induced malignancies, was awarded the Nobel Prize in Physiology or Medicine in 2008 for his discovery of human papilloma viruses causing cervical cancer. He studied Medicine at the Universities of Bonn, Hamburg and Düsseldorf and did his Postdoctoral Fellowship at the Institute of Microbiology in Dü'fcsseldorf, before becoming an Assistant Professor in the Virus Laboratories of the Children’s Hospital in Philadelphia. Prof zur Hausen was a Senior Scientist at the University of Würzburg’s Institute of Virology and Chairman and Professor of Virology at the University of ErlangenNürnberg. He received numerous national and international awards, including the Robert-Koch-Prize, the Charles S. Mott Prize of the General Motors Cancer Research Foundation, and the Federation of the European Cancer Societies Clinical Research Award. He is an elected member of various academies, such as LEOPOLDINA, Academia Europaea, Heidelberg Academy of Sciences, Polish Academy of Sciences, Institute of Medicine of the National Academy of Sciences (USA), and of research organisations including EMBO and HUGO. Prof zur Hausen also has memberships in Editorial Boards of several journals and is currently the Editor-in-Chief of the International Journal of Cancer.

CANCER STEM CELLS: FACT OR FICTION 31 July 2009

Distinguished Speaker Dr John Dick Professor of Molecular Genetics, University of Toronto Program Director, Cancer Stem Cells-GENESIS Ontario Institute for Cancer Research Canada Research Chair, Stem Cell Biology

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Dr John Dick is currently Professor of Molecular Genetics at the University of Toronto, Program Director in Cancer Stem Cells-GENESIS Ontario Institute for Cancer Research, and Canada Research Chair in Stem Cell Biology. He was appointed Senior Scientist of the University Health Network in the Research Institutes of the Toronto General and Princess Margaret Hospital as well as the McEwen Centre for Regenerative Medicine in October 2002. Dr Dick’s research focus on normal human blood and leukaemic stem cells has greatly advanced the understanding of leukaemia’s origins. Elected as a Fellow of the Royal Society of Canada Canadian Academy of Science in 2004, Dr Dick’s research has been recognised by several major awards including: the 1997 Michael Smith Award of Excellence (MRC), 2000 Robert Nobel Prize (NCI Canada), 2002 Herman Boerhaave Medal (Leiden University), 2005 William Dameshek Prize (American Society of Hematology), 2007 Metcalf Lecture (International Society for Experimental Hematology), 2007 Premier’s Summit Award in Medical Research and 2008 Clowes Award (American Association for Cancer Research).


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

PROTON THERAPY: THE FUTURE OF RADIATION THERAPY OR A PASSING FAD? 6 August 2009

Distinguished Speaker Dr Jerry Slater Professor and Chairman, Department of Radiation Medicine, Loma Linda University

Dr Jerry Slater, Professor and Chairman of the Department of Radiation Medicine at Loma Linda University (LLU), is one of the pioneers of hospital-based proton radiation therapy. He designed the treatment protocols under which proton radiation treatment was initiated at Loma Linda University Medical Center (LLUMC) in 1990, and has since led the clinical applications and research at the center. A graduate of LLU School of Medicine, Dr Slater took residency training in M.D. Anderson Hospital and Tumor Institute, Houston, followed by a fellowship in radiation oncology at Massachusetts General Hospital and Harvard Cyclotron Laboratory, Boston. He has authored or co-authored numerous articles in peerreviewed journals, several book chapters and presentations. Dr Slater also holds appointments at several other medical institutions in southern California, and is active in many national and regional cancer and radiation-therapy committees as well as institutional committees at LLU. Dr Slater’s professional pursuit has been in the use and optimisation of radiation therapy, of which proton-beam irradiation is one component. He has led clinical studies of proton therapy for many cancers, investigations of proton and combined-modality treatment of cancers and other diseases in a myriad of anatomic sites.

PHYSIOLOGICAL FUNCTIONS OF DIOXIN (ARYL HYDROCARBON) RECEPTOR, A MULTI-FUNCTIONAL REGULATOR THAT SENSES AND RESPONDS TO ENVIRONMENTAL STIMULI 3 December 2009

Distinguished Speaker Prof Yoshiaki FujiiKuriyama Professor Emeritus, Tohoku University Adjunct Professor, Medical Research Institute, Tokyo Medical and Dental University Visiting Scientist, Institute of Molecular and Cellular Biosciences, University of Tokyo

Prof Yoshiaki Fujii-Kuriyama is best known for his work on the aryl-hydrocarbon receptor, a human gene which may also act as a tumour suppressor, and cytochrome P450 for xenobiotic metabolism. He graduated from the University of Tokyo, where he did his Bachelor’s and Master’s degree in Science before pursuing his doctoral degree at Osaka University. After his PhD, he took up the job as a Research Associate at the Rockefeller University in New York City where he focused on Cell Biology. He returned to Japan in 1975 and assumed the post of an Instructor at the Kansai Medical University, a Member of Cancer Institute, Japanese Foundation of Cancer Research and a Professor of Tohoku University. Currently, Prof Fujii-Kuriyama is a Professor Emeritus of Tohoku University, an Adjunct Professor at the Medical Research Institute of the Tokyo Medical and Dental University as well as a Visiting Scientist of the Institute of Molecular and Cellular Biosciences at the University of Tokyo. He has about 250 papers published in leading medical journals. He is a recipient of the Princess Takamatsu Cancer Research Award, which is given to scientists who have made significant contributions to fundamental and clinical research on cancer.

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TISSUE-BASED MOLECULAR PATHOLOGY – THE KEY TO TARGETED THERAPY OF CANCER 2 March 2010

Distinguished Speaker Dr Manfred Dietel Professor, Anatomic and Surgical Pathology Director, Institute of Pathology, Charité University Hospital Berlin, Humboldt-University

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Dr Manfred Dietel is currently the Professor of Anatomic and Surgical Pathology and Director of the Institute of Pathology, Charité University Hospital Berlin, Humboldt-University. He is an expert in Diagnostic Pathology and works on more than 60,000 biopsies and surgical specimens each year. This includes the application of immunohistochemistry, electron microscopy, Polymerase Chain Reaction (PCR) based molecular diagnostic (clonality testing, detection of microorganisms) and comparative genomic hybridisation during his stints at the University Hospital Charité and affiliated hospitals. Dr Dietel’s focus is in pathology of gynaecology, breast, lung, gastro-intestinum, kidney, urogenital tract, infectious diseases and soft tissues. He has authored more than 200 peer review articles and published chapters for two editions of HARRISONS Internal Medicine, German Editions. Dr Dietel is on the editorial board of many scientific journals including Virchow’s Archiv, Folia Histochemica et Cytobiologica, Pathology Research and Practice and Veröffentlichungen aus der Pathologie. His research methods of interest include cell culture, immunocytochemistry, electron microscopy, DNAcytophotometry, in-situ hybridisation, PCR, molecular pathology, LOH analyses, DNA-arrays, methylation arrays, telepathology, and virtual microscopy.


National Cancer Centre Singapore HUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Research Support Groups

The following units provide administrative and operational support to the Humphrey Oei Institute of Cancer Research of the National Cancer Centre Singapore. Research Division Administration

Grants Management

Audrey-Anne Oei

Connie Cheng Siew Khim

Operations and Core Facilities

Research Finance

Justine Tan Siew Wee Gerald Chua Wei Peng Esabelle Yam Lo Yan Christine Teo Chwee Teng

Cassy Yeo Yoke Mei Jessie Koh Puay Heng Yvonne Kweh Bee Lian Rebecca Tan Li Leng Gwee Hui Eng Tan Siew Kim

Purchasing and Store Justine Tan Siew Wee Kathy Koo Mei Cheng Jordan Tan Yih Haur

Library Ho Shih Yao Mary Tan Nga Khoon

Safety Office Wan Mustaffa bin Wan Chik

Development

Media Prep / Glassware

Patrick Yuen Tat Yan Teo Eng Seng

Wan Mustaffa bin Wan Chik Wendy Tan Ah Yang

Specific Pathogen-Free Unit / Animal Holding Facility Jennifer Devera Germono Magdalene Lim Hiong Lan Jamaludin Bin Jantan Rajeswarie Jeyaram Arifin Bin Basir > 147


National Cancer Centre Singapore 11 Hospital Drive Singapore 169610 Tel: (65) 6436 8000 Fax: (65) 6225 6283 www.nccs.com.sg Reg No 199801562Z

NCCS Humphrey Oei Institute of Cancer Research Brochure  

This brochure contains information of NCCS' research between 2007 and 2010.

NCCS Humphrey Oei Institute of Cancer Research Brochure  

This brochure contains information of NCCS' research between 2007 and 2010.

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