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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Today’s Research Tomorrow’s Cure


Contents Director’s Message

3

NCCS Board Members

4

NCCS Research Committee

5

Donor Quotes

7

Lab Programmes

9

Publications in FY2006

49

International Conferences

59

Local Conferences

61

Invited Lectures

62

Recognition

64

International Collaborators

67

Local Collaborators

72

Manpower Development FY2006

78

Distinguished Lecture Series

80


Spectrum of life

The autofluorescence of bladder cancer captured using a multiphoton laser confocal microscope.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Director’s Message

The Humphrey Oei Institute of Cancer Research embodies our belief that patient-oriented research is the way to tackle cancer and that “Today’s research” will be “Tomorrow’s cure”. Unless we have a good knowledge and understanding of the various types of cancers, the disease will continue to plague and haunt us and the generations to come. We need to find ways to prevent as well as to recognize early disease. Very often it is the early detection that saves lives. Cancer accounts for approximately 30 per cent of all deaths in Singapore, making it the country’s top killer disease. Today, these figures would have increased if not for the efforts of the NCCS and other agencies in successfully gaining an upper hand in tackling the disease. Apart from creating a greater awareness through public education, the medical specialists have been successful in treating and curing more people through medical advances. In our quest to achieve world-class research, NCCS has collaborated with reputable overseas institutions for a two-way exchange of know-how. Our research efforts have also been acclaimed by the medical fraternity overseas with publications in leading peer reviewed international journals like the Cell, Nature Cell Biology, New England Journal of Medicine, Lancet, Journal of Clinical Oncology, Oncogene and Cancer Research. In addition to the increasing number of high impact research publications, the Institute has attracted over $22.5 million in competitive research funding in FY 2006. The work of our research staff brings with it the solemn promise of better research and evidence-based care to the patients we serve. It also brings with it our commitment and accountability to all who support our Institute’s research endeavours. I am fully confident that through the Humphrey Oei Institute of Cancer Research we would contribute to Singapore’s aim of developing world-class research in clinical and translational medicine for the good of mankind.

Prof Soo Khee Chee Director, NCCS

Director’s Message




National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

NCCS Board Members

NCCS RESEARCH FUND BOARD OF TRUSTEES Chairman Dr Charles Toh Consultant Cardiologist, Charles Toh Clinic

Members Prof Tan Ser Kiat Group Chief Executive Officer, Singapore Heath Services Prof Soo Khee Chee Director, National Cancer Centre Singapore Mr Ng Boon Yew Chairman, Raffles Campus Pte Ltd Mr Sim Kee Boon Director, Temasek Holdings Pte Ltd Mr Nicky Tan Director, Ntan Corporate Advisory Pte Ltd

NCCS Scientific Advisory Board Prof Kie-Kian Ang Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center Prof Arnold J Levine Institute for Advanced Study, Princeton Prof Alan P Venook Division of Medical Oncology, University of California, San Francisco



NCCS Board Members


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

NCCS RESEARCH COMMITTEE

CHAIRMAN Prof Kon Oi Lian Head, Division of Medical Sciences

MEMBERS Prof Soo Khee Chee (Ex-officio)

Dr Koo Wen Hsin

Director, National Cancer Centre Singapore

Head, Department of Medical Oncology

Prof Malcolm Paterson (Ex-officio)

Dr Koong Heng Nung

Scientific Director, Singapore Health Services

Acting Head, Department of Surgical Oncology

Dr Nicholas Tay (Ex-officio)

Dr Vijay Kumar Sethi

Chief Operating Officer

Head, Department of Radiation Oncology

Dr Cynthia Goh Head, Department of Palliative Medicine Prof Hui Kam Man Head, Division of Cellular & Molecular Research Dr James Khoo

Dr Joseph Wee Head, Division of Clinical Trials & Epidemiological Sciences Ms Audrey-Anne Oei Senior Manager, Research Administration

Head, Department of Oncologic Imaging

SECRETARIAT Ms Doris Ma Secretary, Division of Medical Sciences

NCCs RESEARCH COMMITTEE




Blazing Trail of light

The autofluorescence of bladder tumour blood vessels captured using a multiphoton laser confocal microscope.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Donor Quotes

“Genetic studies of cancer cells aided by computer technology may provide a means for early detection of cancer. We believe that funding is needed to broaden the database and validate results that have been achieved so far.” Donor, In Memory of Mdm Bek Chai Heah

“We hope that this donation from one man, our founder, Tan Sri Tan Chin Tuan, in response to an appeal from one man, Prof Soo Khee Chee will benefit the many thousands who suffer from cancer.” Ms Chew Gek Khim, The Tan Chin Tuan Foundation

“Funding cancer research is in line with our vision to maximise benefit to society. We believe people of all races, across different countries and generations can stand to gain from NCCS’ research.” Mr Goh Cheng Liang, Goh Foundation

Donor Quotes




From bench to b e d s i d e

Dr Toh Han Chong’s laboratory focuses on bench-to-bedside cancer therapeutics by immune-based strategies and molecular therapies.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF APPLIED HUMAN GENETICS

The Laboratory of Applied Human Genetics focuses on (a) gastric cancer research; and (b) developing cell-based treatments 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.

Oi Lian KON Principal Investigator & Head, Division of Medical Sciences

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.

MBBS, FRCPC Diplomate ABIM, MD

dmskol@nccs.com.sg

RESEARCH STAFF Nelson K.F. CHEN Tiannan GUO Sivalingam JAICHANDRAN Cheryl I.P. LEE Louise S.S. LEE Siew Hong LEONG Wai Har NG

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 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 individuals at high risk of developing gastric cancer; and (d) identify and develop new chemical and biological agents to complement surgical resection – currently the only curative treatment. We have a keen interest in mapping the gastric oncogenome through integrated analysis of global profiles of copy number aberrations, recurrent chromosome breakpoints, mRNA and microRNA expression. Work on putative gastric cancer stem cells focuses on documenting the phenotype of side population cells in a panel of 18 human gastric cancer cell lines. With our collaborators, the gastric proteome and phosphoproteome is being characterised as another entree into the molecular pathways of gastric oncogenesis. We envisage that proteomic data may yield clinically useful biomarkers and novel druggable targets.

Lab Programmes




National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

SELECTED PUBLICATIONS Chen NKF, Jaichandran S, Tan SY, Kon OL

Figure 1: Gastric cancer xenograft.

Figure 2: Gastric cancer histomorphology.

Cell-Based Treatment of Metabolic Disorders Our team has developed electrotransfer of nonviral vector DNA into primary hepatocytes for autologous implantation into pre-clinical models of diabetes (pigs and non-human primates) with significant and durable efficacy. This work is being extended to exploring primary mesenchymal stem cells from different tissue sources as cellular vehicles for physiological insulin secretion. Another metabolic disorder of interest is haemophilia A for which we are pursuing sitespecific integration of factor VIII cDNA into primary human cells. Characterisation of vector integration sites and the consequences thereof, in vivo engraftment and tumorigenicity studies are in progress. We expect to determine the capacity of stably integrated primary cells for phenotypic correction of murine factor VIII deficiency.

Plasmid-electroporated primary hepatocytes acquire quasiphysiological secretion of human insulin and restore euglycemia in diabetic mice. Gene Ther. (2005) 12:655-667. Aggarwal A, Leong SH, Lee C, Kon OL and Tan P Wavelet transformations of tumor expression profiles reveals a pervasive genome-wide imprinting of aneuploidy on the cancer transcriptome. Cancer Res. (2005) 65:186-194. Jaichandran S, Yap STB, Khoo ABM, Ho LP, Tien SL, Kon OL In vivo liver electroporation: optimisation and demonstration of therapeutic efficacy. Hum. Gene Ther. (2006) 17:362-375. Png AEH, Choo KW, Lee CIP, Leong SH, Kon OL Primer design for whole genome amplification using genetic algorithms. In Silico Biology (2006) 6:0047.

Figure 3: High-resolution copy number profiles of chromosome 17 in human gastric cancer. 1000

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An isothermal primer extension method for whole genome amplification of fresh and degraded DNA: applications in comparative genomic hybridisation, genotyping and mutation screening. Nature Protocols (2006) 1:2185-2194.

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Figure 5: Glycemic correction in diabetic Yorkshire pigs implanted with autologous primary hepatocytes modified by electrotransfer of a nonviral vector expressing human insulin regulated by a bifunctional promoter.

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Lab Programmes

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Figure 4: Side population analysis of a gastric cancer cell line.

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Lee CIP, Leong SH, Png AEH, Choo KW, Syn C, Lim DTH, Law HY, Kon OL

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

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 & 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. Molecular pharmacological studies of glioma chemotherapy 2. Cancer Stem Cells in the Brain

Meng Cheong WONG Principal Investigator MBBS, MMed, MRCP, Dip. Amer. Bd. Neur., FRCP, FAMS, FAAN

dmswmc@nccs.com.sg

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.

RESEARCH STAFF

Our team works on two important pathways of DNA damage induced cell signaling:

Congju ZHU (PhD)

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.) plays a vital role in mediating TMZ cytotoxicity. Gliomas often have a dysregulated survival signaling (mutated PTEN, EGFR and PI3K/ mTOR etc.) which significantly confers chemoresistance.

Khong Bee KANG (PhD) Jelissa S.Y. CHENG Ting Ting WANG Siaw Wei TENG Christine Q.H. GAO

By using quiescent and proliferating glioma cell models, we are investigating the interaction of DNA repair and cell survival signaling in glioma chemoresistance. We seek to dissect these important pathways to provide novel insights into the mechanism of DNA damage induced tumour cell killing.

II. Epithelial cell transforming sequence 2 (ECT2) and checkpoint control. ECT2 is an oncoprotein, which transforms fibroblast cells following N-terminal truncation. We have found that ECT2 has novel functions in DNA damage induced checkpoint control as well as normal cell cycle progression.

Currently, we are defining the role of ECT2 in G1/S cell cycle transition and S-phase checkpoint control, which are two critical cellular signaling events underpinning a variety of human malignancies and chemosensitivity. Our study of ECT2 will contribute to understanding of glioma malignancy, towards improving glioma chemosensitivity.

Figure 1: MRI Brain Scans – Malignant Glioma. (a) Pre-Chemotheraphy and (b) Post-Chemotheraphy.

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

undifferentiated neurospheres

differentiated gliomas

SELECTED PUBLICATIONS 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: 464-470.

Figure 2: Growth of primary culture from brain tumour tissues as undifferentiated neurospheres and differentiated glioma cells. CD 133

NESTIN

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. Zhu CJ, Li YB, Wong MC Expression of antisense bcl-2 cDNA abolishes tumorigenicity and enhances chemosensitivity of human malignant glioma cells.

TuJI (NEURON)

O4 (OLIGODENDROCYTE)

GFAP (ASTROCYTE)

J. Neurosci. Res. (2003) 74:60-66. Moore XL, Lu J, Sun L, Zhu CJ, Tan P, Wong MC Endothelial progenitor cells “homing” specificity to brain tumors. Gene Ther. (2004) 11:811-818.

Figure 3: Immunofluorescence staining of brain tumour stem cells showing undifferentiated state (CD133 and nestin) and differentiated progenies (neuron, oligodendrocyte, astrocyte)

Cancer Stem Cells in the Brain 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 selfrenewal, contributing to tumorigenesis. Our lab has established several techniques necessary for isolation of clonal Brain Tumour Stem Cells (BTSCs). We have successfully isolated and characterized cancer stem cells from our patients’ primary glioma brain tumors and shown their enhanced ability to pump out many toxic chemotherapeutic drugs, as well as enhanced resistance to radiation. Our study of these important BTSCs will seek to identify novel targets for better cancer treatment so as to eradicate chemoradioresistance, the primary current cause of relapse and fatality.

Conclusion The Brain Tumour Research Laboratory works closely with clinicians, including neurooncologists, neurosurgeons, radiation oncologists and other colleagues to improve molecular and cellular characterization of brain tumors in our local population, and to improve chemotherapy and biological based therapies (e.g. anti-angiogenic, 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.

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Lab Programmes

Ty AU, See SJ, Rao JP, Khoo JB, Wong MC Oligodendroglial tumor chemotherapy using “decreaseddose-intensity” PCV: a Singapore experience. Neurology (2006) (66)2:247-249. Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu C, Wong MC 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. (2007) 67(3):888-896.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF MOLECULAR ONCOLOGY

Breast cancer is the most common cancer among women in Singapore, with the incidence on a continuing upward trend. Our group analyses known breast cancer susceptibility genes to assess the risk of developing breast and ovarian cancer while concurrently improving on existing testing methods. In addition to analyzing known cancer genes, our group is utilizing genetic and genomic approaches to identify novel cancer related genes.

Risk Assessment for Breast Cancer Ann S.G. LEE Principal Investigator BSc (Hons), MSc, DPhil (Oxon)

dmslsg@nccs.com.sg

Breast cancer is the most common cancer among women in Singapore, with an agestandardised rate at 53.1 per 100,000 per year, which translates to approximately 1000 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 some patients with hereditary breast and ovarian cancer. Women who carry a mutated BRCA1 or BRCA2 gene have a 40 to 80% risk of developing breast cancer by age 70. In order to assess the risk of breast and ovarian cancers, our laboratory has a research protocol which involves the genetic screening of mutations in the BRCA1 and BRCA2 genes using molecular techniques and computational tools. Our research goal is to develop strategies that can improve the detection rate of mutations in our local Asian population.

Figure 1: Detection of an exon 13 rearrangement in the BRCA1 gene using multiplex ligation-dependent probe amplification (MLPA). Arrows indicate the peak for exon 13. (a) Exon 13 duplication with elevated peak,

(b) Result for a normal control.

Eric YAP Adjunct Principal Investigator MBBS (Hons), DPhil (Oxon)

ericyap@dso.org.sg

RESEARCH STAFF

8.46 kb duplication

Irene H.K. LIM Danny C.T. ONG Yar Chze GAN

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Figure 2: Schematic diagram showing a 8.46kb Alu-mediated BRCA1 exon 13 duplication. This duplication was initially detected using the multiplex ligation-dependent probe amplification (MLPA) method. AluSp in intron 12 (grey); AluSq in intron 13 (black).

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Identifying Novel Cancer Related Genes In addition to studying known cancer related genes, our laboratory is investigating genetic aberrations on chromosome 11 in leukemias, breast and colorectal cancers, in order to identify novel tumour suppressor genes. Tumour suppressors act as “brakes” in cells, preventing the occurrence of uncontrolled cell division observed in cancer cells.

SELECTED PUBLICATIONS Lee AS*, Seo YC, Chang APC, Tohari S, Eu KW, Seow-Choen F, McGee JO’D

We have detected high frequencies of chromosomal losses on chromosome II in several tumour types including breast cancer, suggesting that a tumour suppressor gene might be lost in that chromosomal region. Genetic and genomic technologies, such as array CGH analysis and fluorescence in situ hybridization (FISH) are being used to identify candidate tumour suppressor genes.

Detailed deletion mapping at chromosome 11q23 in colorectal carcinoma.

Identification of a candidate tumour suppressor gene and elucidating its function would be potentially important for the understanding of the molecular basis of tumorigenesis, and in gene therapy through the restoration of the functional tumour suppressor.

Lee AS*, Ho GH, Oh PC, Balram C, Ooi LL, Lim DTH, Wong CY, Hong GS

Molecular Diagnostic Technologies

Hum. Mutat. (2003) 22:178. Mutation in Brief #633 (Online) 1-8.

The translation of molecular genetic methods from research to clinical service requires documentable improvements in cost-effectiveness, reproducibility, usability, quality and clinical utility. In this regard, novel methods for mutation screening and genotyping, such as rapid thermal denaturation analysis and novel platforms including microfluidic PCRchips have been developed. These complement the discovery, validation and exploitation of new biomarkers and their molecular assays based on bioinformatic analysis of human and microbial genomes.

Molecular Genetic Studies on Mycobacterium Tuberculosis Multidrug-resistant tuberculosis (MDR-TB) is becoming an increasing global problem, with an estimated 424,203 new cases diagnosed in the year 2004. In an effort to understand the molecular basis of drug resistance of TB in Singapore, we have employed molecular tools to screen for mutations in all known genes involved in drug resistance of TB. The genetic diversity of TB in Singapore has been examined using genotyping strategies for strain identification, in collaboration with the Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore. By using a variety of genetic typing methods, a high power of discrimination of TB genotypes has been achieved. We are currently investigating the relationships between genotype, phenotype and the mutational spectrum of drug resistant TB. The aim is to determine if certain strains may have an enhanced capacity for drug resistance or transmission. This will aid our understanding of the transmission of tuberculosis with the potential to influence control and prevention strategies for tuberculosis not only locally but also in other countries with similar strains.

Br. J. Cancer (2000) 83:750-755.

Founder mutation in the BRCA1 gene in Malay breast cancer patients from Singapore.

Sun YJ, Lee AS, Ng ST, Ravindran S, Kremer K, Bellamy R, Wong SY, van Soolingen D, Supply P, Paton NI Characterization of ancestral Mycobactrium tuberculosis by multiple genetic markers and proposal of genotyping strategy. J. Clin. Microbiol. (2004) 42:5058-5064. Yap KPL, Ang P, Lim IHK, Ho GH, Lee AS* Detection of a novel Alu-mediated BRCA1 exon 13 duplication in Chinese breast cancer patients and implications for genetic testing. Clin. Genet. (2006) 70:80-82. Lai PS, Cheah PY, Kadam P, Chua CL, Lie DK, Li HH, EuKW, Seow-Choen F, Lee AS* Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas. Int. J. Cancer (2006) 119:1061-1066. Toh HC, Teo M, Ong KW, Lee V, Chan E, Lee AS, Vathsala A

normal 11

Use of sirolimus for Epstein-Barr virus-positive smooth-muscle tumour.

der(4)t4;11) der(11)t(4;11)

Lancet Oncol. (2006) 7(11):955-957. *Corresponding author.

Figure 3: FISH analysis using BAC probes to chromosome 11.

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Lab Programmes

Figure 4: Array CGH analysis.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF CELL THERAPY AND CANCER VACCINE

Our laboratory focuses on bench-to-bedside cancer therapeutics by immune-based strategies and molecular therapies. We have developed a cell therapy programme in the form of non-myeloablative blood stem cell transplantation +/- delayed donor lymphocyte infusions for solid tumors. An institution-approved clinical protocol for nasopharyngeal cancer (NPC) is presently accruing. Our interim results have been presented at the American Society of Clinical Oncology meeting in 2006 and the updated results at the Keystone Symposium in Canada in March-April 2007.

Han Chong TOH Associate Investigator BSc, MBBChir, FRCP, FAMS

dmothc@nccs.com.sg

RESEARCH STAFF Marissa TEO (PhD) Peter W.W. WANG (PhD) Yee Peng PHOON

This year, in partnership with the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. we will be developing a clinical trials and translational research programme for NPC patients using adoptive EBV-specific T cell therapy as a therapeutic platform. Our laboratory is also collaborating with the Department of Renal Medicine at the Singapore General Hospital, to study the molecular components of a rare EBV-related cancer, the EBV+ smooth muscle tumour. Our other interest is in cancer vaccines. We have completed a Phase II clinical trial of an allogeneic lysate-pulsed dendritic cell (DC) cancer vaccine for patients with advanced colorectal cancer. We are also performing a series of translational research biomarker studies as part of this DC vaccine trial. We will be starting another clinical trial of autologous DC transduced with a replicationdeficient Ad5f35 adenoviral vector encoding a fusion LMP-1 / LMP-2 transgene in patients with NPC.

Kelly TEO Ma Yatanar SOE

Figure 1: Dendritic Cell Vaccine

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

The other vaccine study that we are engaged in involves constructing a polyepitope vaccine from selected immunogenic peptide sequences of the tumour antigen human telomerase (tert) in fusion with other ‘adjuvant’ genes to potentiate the immune system. Pre-clinical in vitro studies to test the efficacy of this novel construct are ongoing. We are also involved in translational research projects in hepatocellular carcinoma (HCC). We have carried out various studies to investigate prognostic markers of HCC, both in the intrinsic tumour (seed) and the surrounding microenvironment (soil). In one such study, which will be presented at an international cancer conference, 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 analyzing various immunologic parameters and molecular biomarkers in HCC are ongoing. We are currently 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.

(a)

SELECTED PUBLICATIONS Duan Z, Feller A, Toh HC, Makastorsis T, Seiden MV TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line. Gene (1999) 229:75-81. Toh HC, McAfee SL, Sackstein R, Multani P, Cox BF, Colby C, Spitzer TR High dose (HD) cyclophosphamide + carboplatin and interleukin-2 (IL2) activated autologous peripheral blood stem cell transplantation (PBSCT) followed by subcutaneous (SC) IL2 therapy in metastatic breast carcinoma (MBC) – A phase II study. Bone Marrow Transplant. (2000) 25(1):19-24.

(c)

You Z, Huang X, Hester J, Toh HC, Chen SY Targeting dendritic cells to enhance DNA vaccine potency. Cancer Res. (2001) 61:3704-3711. Peri-tumoral (200x)

Normal (200x) (b)

Toh HC, Teo M, Ong KW, Lee V, Chan E, Lee AS, Vathsala A Use of sirolimus for Epstein Barr virus-positive smooth-muscle tumour.

(d)

Lancet Oncol. (2006) 7(11):955-7. Toh HC, Tan EH, Thng CH, Yap SP, Lee KM, Phoon YP, Chua S, Soe Y, Hee SW, Sun L Tumour (200x)

Peri-tumoral (400x)

Figure 2: CD3+Foxp3+ regulatory T cells (Treg) double immunoenzymatic staining. CD3+ T cells are in blue: FoxP3+ cells are in brown (a) In normal region, only one CD3+Foxp3+ Treg cell is observed (indicated by ). (b) In tumour region, more CD3+Foxp3+ Treg cells are observed as compared to normal region (indicated by ). (c) In peri-tumoral region, significant increase in the number of CD3+Foxp3+ Treg cells as compared to both normal and tumour regions (shown in brown). (d) This 400x image of peri-tumoral region clearly shows the double-staining of CD3+ (blue) and Foxp3+ (brown) of Treg cells.

Nonmyeloablative allogeneic blood stem cell transplantation (NMBSCT) +/- donor lymphocyte infusion (DLI) for chemorefractory advanced nasopharyngeal carcinoma (NPC). Proceedings of the American Society of Clinical Oncology (2006) Vol 24, June Supplement, 2549. Teo M, Huynh H, Hee SW, Wang P, Quek R, Toh HC FOXO3a predicts for survival and its phosporylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma. Proceedings of the American Society of Clinical Oncology (2007)

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Lab Programmes


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

TAN CHIN TUAN LABORATORY OF OPTICAL IMAGING AND PHOTODYNAMIC THERAPY The Laboratory of Optical Imaging and Photodynamic Therapy of Cancer is developing novel non-invasive optical methods for cancer diagnosis and therapy for oral and bladder cancer. The novel optical methods being investigated are endomicroscopy, surface enhanced Raman spectroscopy, optical imaging of nanogold conjugated biomarkers as contrast agents in optical coherence tomography (OCT ) and reflectance imaging. These novel optical methods are compared with fluorescence detection methods currently used in the NCCS and SGH clinics. The laboratory is also investigating the treatment of head and neck, and bladder cancers using novel formulations of photosensitizers.

Khee Chee SOO Principal Investigator & Director, National Cancer Centre Singapore

We are the pioneers in the area of clinical applications of both Fluorescence Diagnosis and Photodynamic Treatment in Singapore. The focus of this laboratory is to investigate minimally invasive methods in cancer detection and therapy using biophotonics applications and nanotechnology.

MBBS, MD, FRACS, FACS, FAMS

admskc@nccs.com.sg

Malini Carolene OLIVO Co-Principal Investigator BSc, BEd (Hon), PhD

dmsmcd@nccs.com.sg

RESEARCH STAFF Patricia S.P. THONG (PhD) William W.L. CHIN Kiang Wei KHO

Early Cancer Detection Using Optical Imaging Techniques We have a multidisciplinary, highly interactive research environment comprising biologists and biophysicists. We are currently employing optical imaging techniques to investigate bladder and o r a l cancers. Our major objective is to devise optical on-line real time imaging systems. We are also implementing fluorescence / autofluorescence image processing software and endomicroscopic approaches to develop an optical biopsy technique to stage cancer. 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 Surface Enhanced Raman (SER) spectroscopy using 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 life-time imaging to grade cancer histopathologically.

Bhuvaneswari RAMASWAMY Lucky SASIDHARAN

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

SELECTED PUBLICATIONS 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. (In press, 2007). Thong PS, Olivo M, Kho KW, Zheng W, Mancer K, Harris M, Soo KC Laser confocal endomicroscopy as a novel technique for fluorescence diagnostic imaging of the oral cavity. J. Biomedical Optics 12(1), (In press, 2007).

Photodynamic Therapy Using New Generation Photosensitizers and their Formulations In terms of cancer therapy we are investigating the novel use of photosensitizer and light to treat cancer as an alternative modality to radiation therapy in inoperable cancers. Our aim is to develop novel photosensitizers and their formulations for clinical application in headand-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 biology of the tumors. Combination treatment modalities with immunotherapy and anti-angiogenesis therapy to enhance the efficacy of photodynamic therapy are also being investigated. In the area of photobiology, chemiluminescence and bioluminescence techniques are being studied for the purposes of tumour imaging and therapy. In conclusion, PDT is an alternative modality for cancer therapy and is suitable for use in early lesions that are accessible to an endoscope. PDT also offers good cosmetic results with excellent normal tissue regeneration and is non-toxic to normal cells.

Kho KW, Shen ZX, Zeng HC, Soo KC, Olivo M Methods for Preparing SERS-Active Gold Nanoparticle Substrates. Anal. Chem. (2005) 77(22):7462-7471. Chin WW, Heng PW, Lau WK, Bhuvaneswari R and Olivo M The potential application of chlorin e6-PVP in photodynamic therapy. Photochem. Photobiol. Sci. (2006) 5:1031-1037. Kah JC, Kho KW, Lee CG, Sheppard CJ, Shen ZX, Soo KC, Olivo M Early Diagnosis of Oral Cancer based on the Surface Plasmon Resonance of Gold Nanoparticle. Int. J. Nanomedicine (In press, 2007) Du HY, Olivo M, Mahendran R, Huang Q, Shen HM, Ong CN, Bay BH Hypericin photoactivation triggers down-regulation of matrix metalloproteinase-9 expression in well-differentiated human nasopharyngeal cancer cells. Cell Mol. Life Sci. (Epub ahead of print, March 2007)

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Lab Programmes


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF CLINICAL PHARMACOLOGY

Balram CHOWBAY Principal Clinical Pharmacologist PhD

The general interest of this laboratory is in studying the causes and consequences of inherited variation in the activities of drug-metabolizing enzymes and drug transporters. The primary purpose of our research is to identify the molecular genetic causes of interindividual variability in drug metabolism and is aimed at translating the basic pharmacogenetic findings into predictive information pertaining to patient response to drugs. Given that our aim is to integrate the pharmacokinetic and pharmacogenetic data into potential clinical management, we are actively involved in both preclinical and clinical research activities and provide support to phase I/II pharmacokinetic / pharmacodynamic studies in various clinical trials. The 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 analyze drug disposition, gene structure, gene regulation, and allelic variations.

ctebal@nccs.coms.sg

Research Focus RESEARCH STAFF Srinivasa Rao JADA (PhD) Suman LAL Yan Yan LIU Edwin SANDANARAI Viknesvaran SELVARAJAN Xiaochen SHU

Our approach is to integrate the use of pharmacokinetic, pharmacogenetic, molecular biology and analytical techniques on humans, human tissues, animal models, cloned genes and expressed gene products to analyze drug metabolism and drug transport. Both preclinical and clinical research activities in the laboratory are aimed at translating the pharmacokinetic and pharmacogenetic research findings into clinical applications. Understanding the activity and regulation of the expression of drug metabolizing enzymes is crucial for improving drug dosing – leading to optimal safety and efficacy. Current research in the laboratory is focused on studying the genetic variations and expression levels of key drug metabolizing enzymes, such as the cytochrome P450 enzymes and the uridine glucuronosyltransferases, as well as drug transporters involved in the disposition of a vast array of therapeutic agents. We are also actively investigating the impact of functional genetic polymorphisms in the genes encoding the drug metabolizing enzymes and transporters, and their influence on the pharmacokinetics / pharmacodynamics of drugs in cancer patients of different ethnic groups.

Figure 1: The clearance of irinotecan in relation to SLCO1B1 haplotypes in Asian cancer patients.

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Pharmacogenetics of Irinotecan Irinotecan is administered for the treatment of metastatic colon cancer; the major toxicities seen during therapy include life threatening myelosuppression and diarrhoea. Considerable variations in dosing regimens and response to treatment of irinotecan have also been observed among various ethnic groups. One of our major research areas involves understanding the impact of functional polymorphisms in candidate genes across the irinotecan biochemical pathway. We had earlier reported that the (TA)6/7 repeat polymorphism in the promoter region of the UGT1A1 gene failed to show an association with dose limiting toxicity of irinotecan in the Chinese population. Ongoing studies suggest that a multiplicity of genetic polymorphisms in several UGT1A genes as well as drug transporter genes (SLCO1B1; Fig. 1) may be responsible for the observed differences in toxicity profile between Asian and Caucasian patients.

Profiling Doxorubicin-Cyclophosphamide (AC) Metabolism and Transport Although dose intensity of the anticancer agents is a key factor in the adjuvant therapy of breast cancer, providing a regimen that produces little or no serious toxicity is an important therapeutic goal. Present research also includes characterizing the pharmacogenetic profile across the Doxorubicin-Cylcophosphamide metabolic pathways with a focus on newly identified doxorubicin transporter proteins as well as an understanding of their impact on disposition of doxorubicin and cyclophosphamide in breast cancer patients receiving adjuvant chemotherapy.

Warfarin Pharmacogenetics Warfarin is a commonly prescribed oral anticoagulant with wide interindividual variations in therapeutic response despite careful dose titration. Recent studies have shown polymorphisms in genes involved in the uptake of vitamin K (ApoE), reduction of vitamin K epoxide (VKORC1), metabolism of warfarin (CYP2C9 and CYP2C19), and gamma carboxylation (GGCX) to influence the pharmacokinetics and pharmacodynamics of warfarin in patients from different ethnic backgrounds, resulting in variable warfarin dose requirements. Studies in our lab have shown that Indians, in general, require a significantly higher dose of warfarin compared to Chinese and Malay populations. Understanding the causal relationship of these polygenic influences on warfarin dose requirements in patients of different ethnicity may be vital in reducing interpatient variability and optimizing anticoagulant therapy (Fig. 2).

SELECTED PUBLICATIONS Zhou Q, Cheung YB, Jada SR, Lim WT, Kuo WL, Gray JW, Lee AS, Chowbay B EGFR Intron 1 Polymorphism in Asian Populations and its Correlation with EGFR Gene Expression and Amplification in Breast Tumor Tissues. Cancer Biol. Ther. (2006) 5(11):1445-1449. Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, Lee SC, Lim R, Zhou QY, Goh BC, Tan EH, Chowbay B Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet. Genomics (2006) 16(9):683-691. Zhou Q, Olivo M, Lye KY, Moore S, Sharma A, Chowbay B Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models. Cancer Chemother. Pharmacol. (2005) 56(6):569-577. Zhou Q, Sparreboom A, Tan EH, Cheung YB, Lee A, Poon D, Lee EJ, Chowbay B Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. Br. J. Clin. Pharmacol. (2005) 59(4):415-424. Balram C, Zhou SF, Lee EJ An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore. Drug Metab. Rev. (2005) 37(2):327-378 Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients.

Figure 2: Effect of VKORC1 diplotypes on (A) weekly warfarin dose and (B) S-warfarin clearance in patients homozygous for CYP2C9 reference genotype.

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Lab Programmes

Pharmacogenetics (2003) 13(2):89-95.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

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 characterizing some of them.

I. Functional Genomics of Hepatocellular Carcinoma Caroline G.L. LEE Principal Investigator

FAT10

MAD2

DAPI

MAD2/DAPI

PhD

dmslgl@nccs.com.sg

HCT116

Joint Appointments: Associate Professor, Department of Biochemistry, National University of Singapore Associate Professor, Duke-NUS Graduate Medical School

RESEARCH STAFF Zihua WANG

FAT116

Jianwei REN Yu WANG

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

JingBo WANG

(b) markers to identify individuals who are at high risk of developing HCC, or

Baoshuang WANG

(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.

Pui Hoon SEW

CLINICAL ATTACHMENT Grace PANG (MBBS)

Infection by the Hepatitis B virus HBV is predominant in HCC patients in this part of the world. Hence, another research focus of our lab is to examine the role that HBx, a protein in HBV, plays in the carcinogenesis process.

II. Genetics of Drug Response Genes

Differences in drug response between individuals can be due to pharmacokinetic as well as pharmacodynamic variations. As 90% of inter-individual variation consists of single nucleotide polymorphisms (SNPs), SNPs are now commonly examined in the area of population genetics, complex disease associations as well as pharmacogenetics.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

SELECTED PUBLICATIONS Lee CG, Ren J, Cheong IS, Jin R, Ban KH, Ooi LL, Nuchprayoon I, Lee KH, Choti M, Lee LA Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene (2003) 22(17):2592-2603. Tang K, Wong LP, Lee EJ, Chong SS, Lee CG Genomic evidence for recent positive selection at the human MDR1 gene locus.

Thus far, although the majority of pharmacogenetic variations were studied in drug metabolizing enzymes, there is an increasing interest in examining pharmacogenetic variations due to differences in receptor affinity, drug transporters, drug uptake and excretion processes.

Hence, another interest of our lab is to fully characterize the SNPs, haplotype and linkage-disequilibrium profiles of drug response genes including drug transporters, drug metabolizing enzymes, regulators and drug targets in the different ethnic populations in Singapore compared to the Caucasians and African Americans.

We will also try to identify functionally important polymorphisms that will be useful for association studies.

Our approach of identifying functional polymorphisms will be based on principles of natural selection and “survival of the fittest”.

The exodus of mankind from Africa exposed our ancestors to new and different environments and diseases. Polymorphisms in genes that facilitate better adaptation of the individual to the new environment will be retained and have its frequency increased in that population while polymorphisms that are deleterious will be removed and its frequency reduced in that population.

These “signatures of natural selection” left behind in our genome can be utilized to identify functionally important polymorphisms in “adaptive” genes that play a role in enabling the individual to adapt to new environments. We are also in the process of developing a user-friendly cost-effective chip to facilitate the genotyping of these positively selected SNPs so that it can be more readily brought into the clinic. Our ultimate goal is to be able to tailor an individual’s drug regimen to his genetic profile so that drugs can be delivered at the optimal dose with maximum efficacy and minimum adverse effects.

Hum. Mol. Genet. (2004) 13:783-797. 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):2075-2087. Lee AT, Ren J, Wong ET, Ban KH, Lee LA, Lee CG The hepatitis B virus X protein sensitizes HepG2 cells to UV lightinduced DNA damage. J. Biol. Chem. (2005) 280(39): 33525-33535. 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):11413-11421. 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. (In press, 2007)

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Lab Programmes


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Laboratory of Oncoproteomics

Our laboratory uses proteomic approaches to identify proteins that have aberrant expression in: (i) gastric cancer and (ii) dysferlinopathy (an inherited form of muscular dystrophy), with the goal of gaining insights into disease mechanisms and to develop novel diagnostic and therapeutic strategies.

I. Proteomic Approaches for Biomarker Discovery in Gastric Cancer Mac M.F. HO

Principal Investigator DPhil (Oxon)

dmshmf@nccs.com.sg

RESEARCH STAFF

Early detection is thus the single most important factor influencing the outcome for gastric cancer patients. However, there are currently no reliable biomarkers or clinically acceptable techniques to detect early stage gastric cancer.

Biomarkers are important tools for cancer detection, clinical surveillance and treatment. They serve as sentinel hallmarks for the physiological status of the cell at a given time and can be used to monitor disease onset, progression, response to drug therapy, and may even be therapeutic targets themselves.

The identification of informative biomarkers will aid disease diagnosis and ensure early clinical intervention, thereby preventing mortality and reducing morbidity.

The etiology of most gastric cancers is multifactorial and the pathogenesis is believed to involve a multi-stage process in which the normal gastric epithelium evolves through intermediate pre-malignant lesions to eventually overt adenocarcinoma. Despite these well defined histological changes in gastric cancer, the precise initiators and the molecular pathway(s) for gastric carcinogenesis remain poorly understood.

In collaboration with the Kon laboratory (Applied Human Genetics) and clinicians at SGH, we are using proteomic approaches to analyze the protein profiles of malignant, pre-malignant, and non-neoplastic gastric tissues and biofluids. We hypothesize that the transformation from normal gastric epithelium to gastric carcinoma entails a sequence of molecular and genetic changes.

By identifying proteins that show aberrant expression at different histological stages of gastric cancer, we should gain insights into the pathogenic mechanism / pathway of gastric carcinogenesis. In turn, the newly identified proteins may themselves be candidate biomarkers for diagnosis and targets for novel drug therapies.

Siok Yuen KAM Huimin CHUA Kit YUENG

Despite an overall decline in incidence, gastric cancer is still the second leading cause of cancer-related deaths worldwide, accounting for nearly 1 million new cases and more than 700,000 deaths in 2002. Its lethality is mainly due to the late-stage diagnosis, which has a very poor prognosis (5-year survival is 3-10%). By contrast, the 5-year survival rate for early stage gastric cancer is > 90%.

Celine CHUA

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Figure 1: Silver-stained two-dimensional (2D) gels of human stomach proteins from (A) normal gastric tissue and

(B) gastric carcinoma.

SELECTED PUBLICATIONS 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 downregulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. J. Immunol. (2005) 175(9):6219-6225.

Comparison of the 2D protein gels reveals quantitative and qualitative differences between the proteomes of normal gastric tissue and gastric carcinoma. Red circles highlight examples of differentially expressed proteins identified between the two tissue samples.

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):1999-2010.

II. Dissecting the Molecular Apparatus and Pathway for Dysferlin-Mediated Membrane Repair

Disruption of the plasma membrane is a common form of injury that can occur under physiological conditions, trauma, during certain types of clinical intervention and some forms of muscular dystrophies (e.g. dysferlinopathy). Repair of disrupted membranes is critical for cell survival.

Dysferlin, a novel skeletal muscle protein, was recently shown to play a role in plasma membrane repair. However, the mechanism of dysferlin-mediated membrane repair is unknown.

In this project, we are interested in elucidating the molecular apparatus and the signaling pathways involved in the membrane repair process.

Towards this end, we have generated a strain of dysferlin-deficient mice via gene targeting, to study the function of dysferlin. In addition, we have identified an inbred line of mice, A/J, which also lacks the dysferlin protein. Both lines of mice develop a progressive muscular dystrophy with histopathological features that closely resemble the human disease.

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To better understand the membrane repair process, we are using genetic and proteomic approaches to analyze tissues from our dysferlin-deficient mouse models. These studies should help identify the components of the membrane repair machinery as well as its signaling pathways. In addition, they will provide a cogent basis to devise new therapeutic strategies for enhancing membrane repair in all forms of membrane disruptions in cell injury.

Lab Programmes

Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown RH Jr, 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):1301-1298. Ho M, Gallardo E, McKenna-Yasek D, De Luna N, Illa I, Brown Jr RH A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann. Neurol. (2002) 51(1):129-133. Ho M, Amato A, & Brown RH Jr Dysferlinopathies in Structural and Molecular Basis of Skeletal Muscle Diseases. (G. Karpati, ed) pp29-32 (2002) ISN Neuropath Press, Basel.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Bek Chai Heah LABORATORY OF CANCER GENOMICS

Revolutionizing Cancer Treatment through personalized and Targeted Therapies

Kam Man HUI Principal Investigator & Head, Division of Cellular & Molecular Research PhD (Northwestern), FRCPath (UK)

cmrhkm@nccs.com.sg

RESEARCH STAFF James ZHENG (PhD) Kia Joo PUAN (PhD) Poi Kiang TAN (PhD) Wen Min LAU Bee Hui LIU Ke SHAO Suk Mei WANG Jessica ZVALEUSKAS

Cancer arises from genetic changes in cells, and it is now recognized as a very complex disease that includes more than 200 different diseases. We choose to focus our efforts on studying important genetic changes associated with human lung, liver, nasopharyngeal, and cervical cancers through the identification of changes to the populations of messenger RNA that occur in these cancer types. To accelerate our effort to identify the molecular and genetic basis of human cancers, we employ global gene expression profiling to systematically explore the universe of genomic changes involved in these types of human cancer. Such changes are often correlated with the alterations of functional proteins produced by tumour cells. The availability of these expression maps that are indicative of the genomic changes of cancer will help us to gain new insights into the biological basis of different types of human cancers, which in turn will help us to develop new molecular diagnostic tests to detect cancer in its early, most treatable stages. Furthermore, by identifying molecules that are specific for cancer, novel targeted therapeutic strategies can be realized. Lung cancer is the major cause of cancer-related mortality in both men and women. We have recently formed the National Lung Cancer Consortium, a unified infrastructure consisting of platform technologies, bioinformatics, and a tumour specimen repository, to pool our expertise in the effort to identify genetic changes and genes that play a vital role in the etiology of human lung cancer. A molecular gene database has been initiated that holds the expression information of thousands of genes for each individual patient’s cancer biopsy. This molecular database will provide a powerful resource in developing strategies to understand the molecular basis of human lung cancer and offer the potential to develop therapeutic strategies. Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with the highest incidence in Southeast Asia and Sub-Saharan Africa. The major etiological and risk factors for HCC have been identified as chronic infection from hepatitis virus, dietary aflatoxin, overloading of iron and alcohol consumption. Besides having a poor prognosis, HCC patients have an extremely high risk of developing recurrent cancer as well as new primary cancers in the residual cirrhotic liver. Currently, the most commonly used marker for diagnosis and prognosis of HCC is serum alphafetoprotein (AFP). However, AFP levels are frequently elevated in other conditions such as hepatitis and toxic liver injury and are therefore not cancer specific. We have initiated a programme to perform gene expression profiling of HCC to identify biomarkers that could potentially be employed for the molecular prediction of HCC recurrent disease at diagnosis. Human nasopharyngeal carcinoma (NPC) has been classified by the World Health Organization (WHO) into three categories according to the degree of differentiation. Asians were reported to have the highest proportion of radio-responsive WHO-II nonkeratinizing and WHO-III undifferentiated carcinomas of the nasopharynx. They have better survival rates compared to African-Americans and Hispanic and non-Hispanic whites, who have higher incidence of the less radio-responsive keratinizing squamous cell carcinomas of the nasopharynx. Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

To study the potential differences in the carcinogenesis between undifferentiated and differentiated human NPC and to identify NPC-specific genes, we have initiated a programme to employ gene profiling to identify and characterize genes that are specific for human undifferentiated NPC. This study will provide a systematic approach to understanding the differences in the molecular mechanisms underlying the carcinogenesis of the keratinizing squamous cell carcinomas of the nasopharynx and the relatively more radio-responsive non-keratinizing carcinomas. Cervical cancer is the second leading cause of cancer mortality in women worldwide. Primary treatment of early stage invasive cervical carcinomas includes surgery and radiation therapy, with radiotherapy or chemoradiotherapy being the standard treatment for locally advanced cervical cancer. However, tumour resistance to chemoradiotherapy in advanced disease is still a serious clinical problem. In our laboratory, we have employed gene expression profiling of human cervical cancer to identify early molecular diagnostic markers as well as to understand the molecular pathway underlying cervical carcinogenesis with the ultimate aim to improve treatment outcome of the disease. Clinical oncology has been impacted strongly by the recent advances in genomics and related technologies. The development of targeted cancer therapies has become a major focus in this field. Gene therapy was initially developed as a strategy to treat monogenic diseases through the replacement of mutated genes with the wild-type counterpart. However, much emphasis has recently been placed on the possibility of applying gene therapy in the treatment of diseases including cancer. In our laboratory, we have synthesized various novel cationic liposomes and nanoparticles for efficient gene delivery into cancer cells to stimulate potent immune responses against cancer. Unlike viral vectors that are usually immunogenic and possess potential oncogenicity and unknown long-term toxicity, cationic liposomes are basically “safe�. They could potentially represent the pharmaceutical formulation of gene medicine that will compete well against conventional pharmaceutical, biological and surgical therapies, by offering improved effectiveness and safety at lower costs. Furthermore, to increase the therapeutic potentials and to reduce toxicity, we are developing gene delivery vehicles that are tagged with tumour-specific molecules as targeting elements. We have also established a programme involving the direct exploitation of naked DNA for gene delivery. The primary advantages of using DNA as immunogens include the ease of determining its purity, stability, easy production, and apparent ability to preferentially generate killer CD8+ T cells, and Th1-based, helper T cells, to provoke long-term antitumour immunity. In this context, we have demonstrated that the introduction of a recombinant gene encoding the human Flt-3L gene into mice could result in the rapid expansion of functional dendritic cells, potent antigen-presenters, in vivo. This strategy could potentially be evolved to efficient protocols for antigen-specific immunotherapy of human malignancies.

SELECTED PUBLICATIONS Tan MGK, Ooi LL, Aw SE, Hui KM Cloning and identification of HDMCP, a novel liver-specific uncoupling protein that is downregulated in human hepatocellular carcinoma. J. Biol. Chem. (2004) 279:45235-45244. Wu XF, Gao H, Pasupathy S, Tan PH, Ooi LL, Hui KM Systemic administration of naked DNA with targeting specificity to mammalian kidneys. Gene Ther. (2005) 12(6),477-486. Lam PY, Lim KS, Wang SM, Hui KM A microarray study to characterize the molecular mechanism of TIMP-3 mediated tumor rejection. Mol. Ther. (2005) 12,144-152. Choy CL, MOK C-L, Hui KM Intramuscular immunization with plasmid coexpressing tumour antigen and Flt-3L results in potent tumour regression. Gene Ther. (2006) 13:245-246. Tan K, Cheang P, Ho IA, Lam PY, Hui KM Nano-sized bio-ceramic particles could function as efficient gene delivery vehicles with target specificity for the spleen. Gene Ther. (In press, 2007). Lau WM, Ho TH, Hui KM p16INK4A -silencing augments DNA damage-induced apoptosis in cervical cancer cells. Oncogene (In press, 2007).

Normal

HCC

Down-regulated Up-regulated

Figure 1: Expression of genes that are found to be altered in human HCC spreads across all the chromosomes.

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Lab Programmes

1 2

3

4

5 6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF MOLECULAR ENDOCRINOLOGY

Novel Therapeutic Approaches for Hepatocellular Carcinoma

The Hung HUYNH Principal Investigator PhD, FRCPath

Hepatocellular Carcinoma (HCC) is the fifth most common malignancies worldwide. Despite the available treatment options, the incidence still nearly equals to the mortality rate for this cancer. The poor efficacy of medical treatment of patients with HCC and the dissatisfaction with such treatment has motivated the development of primary xenografts of HCC to identify effective therapies and to evaluate the efficacy of novel or existing drugs prior to clinical trials. We have successfully developed primary xenografts of HCC in the SCID mouse model directly from resected HCC of patients. This has proven to be an important platform for new drug testing especially in targeted and combined therapies. We are currently working with several pharmaceutical companies and academic institutes to improve therapeutic strategies for HCC.

cmrhth@nccs.com.sg

RESEARCH STAFF Choon Kiat ONG Irene W.L. LAM Jie Hui LIM Tian-yu ZHANG Siok-Lam LIM Ngo Van CHANH

Xenografts of Human Hepatocellular Carcinoma – A Model for Testing Drugs Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with an annual estimation of 667,000 new cases. Despite the available treatment options, the incidence still nearly equals to the mortality rate for this cancer. Approximately, 95.5% of liver cancer patients die within 12 months and the median survival for inoperable HCC is generally about 6 months. While surgery is the only therapy that consistently prolongs survival for HCC, unfortunately, 85-90% of HCC are inoperable. Long-term survival for operable patients is uncommon because of the frequent development of recurrence (as high as 50% at 2 years) and metastasis or the development of new primary tumors. Currently, none of the non-surgical treatment modalities have been conclusively proven to be effective in improving survival rates of inoperable HCC patients. The poor efficacy and the dissatisfaction with current treatments have motivated our research team to develop xenografts of HCC in an immuno-deficient mouse model, directly from tumors of patients. These primary HCC appear to be the only currently available means that permits the propagation of these primary carcinomas. This has proven to be an important platform for new drug testing especially in targeted and combined therapies. Our team works closely with clinical and other scientific collaborators from NCCS as well as from elsewhere, to map out the molecular pathway changes downstream following exposure to several molecular targeted agents. These include vascular endothelial growth factor antibody and extracellular signal-regulated kinase kinase inhibitor, and from this work, we have discovered some unexpected and interesting pathway connectivity.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Our group has also profiled the genes of the primary HCC and found striking similarities in the gene profile when compared to the corresponding xenograft. Therefore, it is likely that this xenograft model of HCC is more accurate and similar to humans as one can get compared to HCC cell line xenografts.

SELECTED PUBLICATIONS

As a result, one patent has been filed and one of the combined therapies is currently in Phase I clinical trial for HCC. With the support from the Singapore Cancer Syndicate, our group has set up the National Xenograft Therapeutic Programme (NXTP) in April 2006. NXTP is fast becoming a recognized industry and academic leader in the area of HCC drug development.

Xenografts of human hepatocellular carcinoma: a useful model for testing drugs.

The NXTP is currently working with several pharmaceutical companies including AstraZeneca, Merck, Bristol-Myers Squibb, and Novartis and academic institutes to improve therapeutic strategies for HCC. Our group’s current research potentially offers clinicians a better way to tailor HCC treatment to the individual patient. Such an approach to therapy promises to be more selective and to reduce side effects and improve quality of life. Over the next 5 years, NXTP aims to:

Huynh H, Soo KC, Chow PK, Panasci L, Tran E

Clin. Cancer Res. (2006) 12:4306-14. Huynh H, Soo KC, Chow PK, Tran E Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther. (2007) 6(1):138-46.

(1) generate a large pool of HCC xenografts; (2) identify and evaluate newly developed molecular targeted compounds for treatment and prevention of HCC; and (3) further document gene expression profiles, growth characteristics, molecular pathology, comprehensive whole-genome mRNA gene expression profiles of patient tumors and their associated xenografts.

Ong CK, Leong C, Tan PH, Van T, Huynh H The role of 5’ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma. Oncogene (2007) 26(8):1155-65. Leong CT, Ong CK, Tay SK, Huynh H Silencing expression of UO-44 (CUZD1) using small interfering RNA sensitizes human ovarian cancer cells to cisplatin in vitro. Oncogene (2007) 26(6):870-80. Huynh H, Chow PK, Soo KC, Panasci L and Nguyen TH

Identification of Targets

Hormonal Therapies

• Microarrays • Antibody-arrays • Proteomics • Western blotting etc

Xenografts

SarCNU-induced G2/M arrest in hepatoma cells is mediated by a p53-independent phosphorylation of cdc-2 at Tyr15. J. Cell. Physiol. (2005) 204:785-791. Huynh H Over-expression of tumour suppressor retinoblastoma 2 protein pRb2/p130) in hepatocellular carcinoma (HCC). Carcinogenesis (2004) 25:1485-1494.

Data Analysis Medical Oncologists for decision

Figure 1: Schematic showing how xenografts are created from primary hepatocellular carcinoma (HCC). The HCC xenografts are grown in mice and are serially transplanted. They are used to identify effective therapies and to evaluate the efficacy of novel or existing drugs prior to clinical trials.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF GENOMIC ONCOLOGY

Cancers between individual patients often display strikingly different types of clinical behaviour including disease aggressiveness and responsiveness to treatment. Unfortunately, many of these differences are currently not predictable using conventional techniques for cancer classification. Our laboratory employs genomeprofiling technologies to identify molecular features of tumors that will enable such predictive classification, and to ultimately provide personalized cancer care.

Research Focus Patrick TAN Adjunct Principal Investigator MD, PhD

cmrtan@nccs.com.sg

Our group focuses on the application of genome and proteome-level targeted technologies to address biological questions in cancer. We are also intrigued by the rapid mutability and genomic plasticity of the cancer genome, and believe that developing whole genome cartographies of tumors will enable us to better understand the molecular basis of cancer and to identify cellular pathways and molecular nodes for intervention. Our specific ongoing projects include :

Joint Appointments: Group Leader, Genome Institute of Singapore Associate Professor, Duke-NUS Graduate Medical School

I. Genomic and Proteomic Discovery of Biomarkers in Breast Cancer

RESEARCH STAFF Kumaresan GANESAN (PhD) Tatiana IVANOVA (PhD)

Breast cancer is the most common malignancy for females in Singapore. In comparison to the US and Europe, breast cancer in Asia tends to present in women at an earlier age. The current reason for this epidemiological difference is not known. A central challenge in the current management of breast cancer lies in the selection of appropriate treatment regimens for individual breast cancer patients, so as to maximize therapeutic benefits while minimizing adverse drug-related outcomes.

Yonghui WU (PhD) Qing Song HOU Julian LEE Ming Hui LEE Angie L.K. TAN Jeanie K.L. WU

A)

Normal

B)

Tumour

Kun YU

Figure 1: Biomarker Discovery in Breast Cancer

C)

Tumour

D)

Tumour

Shown are four breast tissues: 1 normal (A) and 3 tumors (B-C). Tissues were stained with an antibody to RUNX3, identified through an integration of genomic and gene expression information. RUNX3 was observed to be frequently downregulated in breast tumors. For more details, see Wei et al., (2007) Genes Chromosomes and Cancer 46, 288-301)

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Our breast cancer programme focuses on the identification of molecular biomarkers, such as genetic variants, expression signatures, and proteomic patterns, which could aid an oncologist in providing personalized treatment options to individual breast cancer patients. For breast cancer, we have used DNA microarrays to establish a genomic database comprising hundreds of Asian breast cancer samples, and used this information to identify several expression signatures that can accurately predict various clinical parameters (e.g. normal vs malignant, estrogen receptor status, response to tamoxifen) associated with an unknown breast sample. To evaluate the efficacy of these signatures in a busy clinical setting, we are currently conducting a prospective trial using customized microarrays carrying these signatures in patients treated at the National Cancer Centre Singapore.

II. Discovery of Oncogenic Pathways and Processes in Gastric Cancer

Gastric cancer is the second leading cause of global cancer mortality. Despite this, 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. Using a combination of array-based comparative genomic hybridization and expression profiling strategies, we have shown that gastric cancers can be subdivided into distinct molecular subtypes with distinct clinical outcomes. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we have formed an international Gastric Cancer Consortium comprising members from Australia, Hong Kong, Japan and Singapore, to pool expression data from >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 signaling through this receptor may contribute to gastric carcinogenesis. We are currently extending these studies to larger cohorts of gastric cancers to further investigate this possibility.

SELECTED PUBLICATIONS 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(1):232-241. Aggarwal A, Leong SH, Lee C, Kon OL, Tan P Wavelet transformations of tumor expression profiles reveals a pervasive genome-wide imprinting of aneuploidy on the cancer transcriptome. Cancer Res. (2005) 65(1):186-194. Yu K, Lee CH, Tan PH, Hong GS, Wee SB, Wong CY, Tan P A molecular signature of the Nottingham prognostic index in breast cancer. Cancer Res. (2004) 64(9):2962-2968. Yu K, Lee CH, Tan PH, Tan P Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic populations. Clin. Cancer Res. (2004) 10(16):5508-5517. Tay ST, Leong SH, Yu K, Aggarwal A, Tan SY, Lee CH, Wong K, Visvanathan J, Li D, Wong WK, Soo KC, Kon OL, Tan P A combined comparative genomic hybridization and expression microarray analyses of gastric cancer reveals novel molecular subtypes. Cancer Res. (2003) 63:3309-3316.

Figure 2: Systems-Map of Gastric Cancer – Each circle represents a collection of genes that are tightly co-regulated across >300 gastric tissues. For more details see Aggarwal et al., (2006).

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF MOLECULAR CARCINOGENESIS

Tumour formation is a multi-step process involving the deregulation of several 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 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.

Kanaga SABAPATHY Principal Investigator PhD

cmrksb@nccs.com.sg

RESEARCH STAFF Kenneth M.K. LEE (PhD) Anbalagan MOORTHY (PhD) Faina VIKHANSKAYA (PhD) Amy CHUA Iqbal DULLOO Shin Yuen NAM Beng Hooi PHANG Wen Hong TOH Min XIE

The Molecular Basis of Human Cancer The role of the tumour-suppressor genes, p53 and p73 and the proto-oncogene, c-Jun, in tumorigenesis

In order to achieve our goals, we focus on understanding how normal cells respond to various environmental factors, which would determine their cellular fate. In brief, when a cell is subjected to adverse environmental and carcinogenic factors, it has an option of: 1. undergoing programmed cell-death (cellular-suicide) when the damage is irreparable; 2. arresting its progression through the cell cycle, and repair its damaged DNA; 3. ignoring the signals and continue to proliferate. The outcome of this decision is crucial in the development of cancer and hence, the determination of cell fate is a tightly orchestrated process regulated by the interplay of various cellular gene-products. Prominent among these during stress signalling is the proto-oncogene c-Jun, 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, thus leading to uncontrolled growth. Our main objective is to elucidate the biochemical and biological processes that underlie the ability of p53 to act as a tumour suppressor. In particular, we are studying the mechanisms by which the activity of p53 is regulated by environmental agents that cause cellular stress, and the involvement of post-translational modifications of p53 in determining the biological effects of its activation. Mouse-models and genetic screens are employed to achieve these goals.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

In this respect, we are currently developing “knock-in” mouse models for the study of liver cancer, which is prevalent in Asia. Moreover, we are developing an active programme to study the prognostic role of p53 mutations and polymorphisms in cancer therapy. In this regard, our efforts are focused on obtaining valuable information that would allow us to eventually provide a platform for “tailor-made” therapy for each individual cancer patient with a p53 mutation. Unlike p53 which is mutated in more than 50% of all human cancers, its relative, 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. We are focusing on understanding the role and regulation of p73, particularly with reference to its ability to induce cell death. Mouse-models are also being generated to understand the physiological roles of the various p73 forms expressed in cancers. We hope to ‘activate’ p73 in human cancers, thereby harnessing it’s ability to induce cell death in the eradication the disease. Unlike the tumour suppressor genes, the 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. We are trying to understand how c-Jun cooperates with various co-activators in bringing about these diverse effects. 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 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):713-725. Lee MK, Hande MP, Sabapathy K Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis. J. Cell Science (2005) 118(4):819-829. Toh WH, Kyo S, Sabapathy K Relief of p53-mediated telomerase suppression by p73. J. Biol. Chem. (2005) 280(17):17329-17338. Siddique MM, Sabapathy K Trp53-dependent DNA-repair is affected by the codon 72 polymorphism. Oncogene (2006) 25:3489-3500. Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SAG, Sabapathy K

Figure 1: Cancer in mice and man: Role of p53 and p73 in carcinogenesis.

c-Jun promotes cellular survival by suppression of PTEN. Cell, Death & Diffen. (2007) 14(2):218-229 Vikhansyaka F, Lee MK, Mazzoletti M, Broggini M, Sabapathy K Cancer-derived p53 mutants suppress p53-dependent target gene expression – potential mechanism for gain of function of mutant p53. Nucleic Acid Research ( In press, 2007)

Figure 2: The c-Jun/JNK signalling pathway.

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Figure 3: The p53/p73 tumour suppressor pathway.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF GENOME MAINTENANCE

Cancer, at its very core, is a genetic disease. Recently, its molecular underpinnings have been 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.

Malcolm PATERSON Principal Investigator PhD (Tennessee)

malcolm.paterson@singhealth.com.sg

Research in our two labs primarily focuses on undertaking a series of hypothesis-driven, mechanistic studies into various components of GMN. These enquiries 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. Sphase checkpoint in which DNA replication is transiently arrested in response to γ-radiation);

Susan L. LOONG Associate Investigator FRCP (Edinburgh) FRCR (Clinical Oncology) MD (Edinburgh)

trdlle@nccs.com.sg

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 γ- irradiation. This surprising finding implies that PGE2 can act as an extracellular signaling molecule in γ-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 double-strand breaks (DSB) in γ-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;

DNA Damage

RESEARCH STAFF Amuthan GOVINDASAMY (PhD) Wu Meng TAN (MBBS, PhD)

DNA-damage response pathways

Seow Fong YAP (PhD) Cynthia S.K. BOO Joanne JAMES Haslinda Bte KAMIS Jennifer P. NEWMAN

STOP

Cell Cycle control

R.I.P.

Apoptosis

Transcription

DNA Repair

Figure 1

Yogavalli POOBALAN

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

4. A proportion of patients have severe, unexpected reactions to conventional radiation treatment for cancer. We seek to understand the basis for this phenomenon.

To this end, we have established cell lines from such patients: three from Scottish patients with breast or cervical cancer, who developed radiation necrosis after treatment, and a further series from Asian patients with pronounced and early acute morbidity. An ongoing protocol exists to identify additional patients and establish cell lines from their blood lymphocytes.

We have characterized these cell lines. The Scottish cell lines are sensitive to ionizing radiation and have impaired efficacy at rejoining radiation-induced DSB in DNA. Detailed biochemical analysis is underway, to identify the defective repair pathway(s).

The second series of cell lines, upon irradiation, exhibit increased and earlier apoptosis compared to normal controls. They also show increased chromosome instability upon exposure to ionizing radiation. [See Figure 1] We are currently measuring their efficacy at DNA DSB repair.

Selected Publications Mirzayans R, Paterson MC Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment. Environ. Mol. Mutagen (2001) 38:191-199. Lari SU, Al-Khodairy F, Paterson MC Substrate specificity and sequence preference of G:T mismatch repair: incision at G:T, 06-methylguanine:T and G:U mispairs in DNA by human cell extracts. Biochemistry (2002) 41:9248-9255.

Chromosomal Spread with Dicentrics The source patient developed pronounced early and acute morbidity in response to radiation treatment. Derived from this patient’s peripheral blood lymphocytes, the SRH6 cell line exhibits chromosome abnormalities such as dicentrics [arrowed] following lowdose irradiation.

Famulski KS, Al-Hijailan RS, Dobler K, Pienkowska M, Al-Mohanna F, Paterson MC Aberrant sensing of extracellular Ca2+ by cultured ataxia telangiectasia fibroblasts. Oncogene (2003) 22:471-475. Loong SL, Korzh S, Price A Reduced DNA-dependent protein kinase activity in two cell lines derived from adult cancer patients with late radionecrosis. Oncogene (2004) 23:5562-5566.

Figure 2: Fluorescent in situ hybridisation (FISH) of metaphase chromosomes.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF CANCER GENE THERAPY

The main focus of our laboratory is to develop an ideal carrier or gene vector that delivers therapeutic agents into cancer cells effectively. Conventional cancer therapy has its limitations. Surgery may not be the most appropriate treatment since not all regions of the tumors are easily accessible. Other conventional treatments such as radiotherapy and chemotherapy are known to kill normal proliferating cells in addition to the cancerous ones. As a result, patients often suffer from unpleasant side-effects.

Paula Y.P. LAM Principal Investigator PhD cmrlyp@nccs.com.sg

Thus, one of our research objectives is to develop novel vectors that support stable therapeutic gene expression only in tumour cells with uncontrolled cell divisions. Concurrent with these studies, specific cancer antigens are identified and examined for their specific homing potential to tumour cells when incorporated into the envelope coat protein of the newly constructed vectors. Therapeutic genes are also being evaluated for their efficacies in treating different tumour types as the tumour cell blueprint varies from one cell to another.

RESEARCH STAFF

Ivy A.W. HO (PhD) Grace Y. WANG (PhD) Kian Chuan SIA Lv MIAO

Research Focus Our laboratory pursues two complementary areas of research. The first is to develop an ideal carrier or gene vector that delivers therapeutic agents into cancer cells effectively. These vectors should have a large transgene capacity; easy to manipulate; and transgene expression should be tightly regulated and stable. One of these vectors is the herpes simplex viral type-1 amplicon vector. The added advantage of these vectors is that they can be packaged using a helper virus-free packaging system, thus eliciting only a mild immune response. The second area is to pursue further understanding of the roles of stem cells in the progression and development of the neural tumour microenvironment. In particular, neural stem cells exhibit an amazing potential in tumour cell tracking. Deciphering the molecules and mechanisms involved in this tumour tropism is pivotal in the design of therapeutic modalities for gene therapy of human cancers.

I. Design of Novel Viral Vectors As hyperproliferation is a characteristic of malignant tumour cells, the strategy of transducing the resected region with vectors that can be “switched on� once the residual dormant tumour cells start to proliferate, would represent potentially interesting tools for human cancer gene therapy. One way of accomplishing this goal would be to combine cell type-specific and cell cycle regulated gene expression in the vector backbone.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Several modifications have been incorporated into the amplicon vectors to achieve cell cycle-dependant transgene expression and specificities. This was demonstrated in an ectopic mouse model bearing two different tumour cell types (non-hepatocellular carcinoma, left) and (human hepatocellular carcinoma, right) on both flanks (Fig.1). Luciferase reporter gene is under the regulation of both cell cycle-element and human hepatocellular carcinoma (HCC )-specific promoters. Luciferase reporter activities could be detected only in the actively proliferating tumour mass of specific cell types, i.e., HCC cells (right).

20.1

SELECTED PUBLICATIONS

17.2

Lam PY, Sia KC, Khong JH, Geest BD, Lim KS, Ho IA, Wang GY, Miao L, Hung TH, Hui KM

14.4 11.5 Flux = 3780 Ph/s

8.6 5.7

Flux = 296 Ph/s

2.9 0

Figure 1

II. Human tumour and stem cell interactions in the tumour microenvironment The use of neural stem cells for the study of brain development, plasticity and potential gene therapy has been frequently reported. However, most of these studies are based on murine neural stem cells. In our second major investigation, we seek to understand how the inherent biologic properties of neural stem cells may differ from human bone marrow derivedmesenchymal stem cells. In addition, the influence of human bone marrow derived-mesenchymal stem cells (hMSCs) in a tumour microenvironment may also provide further insights into the interplay between cancer stem cells versus normal cells and vice versa. CM-DiI pre-labeled hMSCs (in red) were demonstrated to exhibit tumour tropism, similar to those of neural stem cells (Fig.2). Tumour kinetics was closely monitored by magnetic resonance imaging, haematoxylin and eosin staining, and loss of body weight. Between 14 - 17 days post hMSCs implantation, all the cells were found within the glioma tumour region (as indicated on the right). An interesting structural organization of hMSCs (labeled green) around the glioma cells (labeled red) was observed when the two cell types were co-cultured. Co-cultured hMSCs were found to express glial fibrillary acidic protein indicating possible astrocytic differentiation. The intricate relationship is under investigation. 1st week post glioma 2nd week post glioma Cells inoculation Cells inoculation Injection site

* BM-hMSC

Figure 2

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glioma

An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas. Mol. Ther. (In press, 2007) 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. Hum. Gene Ther. (Epub ahead of print, March 2007) Sia KC, Wang GY, Ho IA, Khor HY, Miao L, Hui KM, Lam PY Optimal purification method for herpes-based viral vectors that confers minimal cytotoxicity for systemic route of vector administration. J. Virol. Methods (2007) 139(2):166-174 Ho IA, Hui KM, Lam PY Targeting proliferating tumor cells via the transcriptional control of therapeutic genes. Cancer Gene Ther. (2006) 13(1):44-52 Lam PY, Lim KS, Wang SM, Hui KM Apoptosis induced by TIMP-3 in glioma cells. Mol. Ther. (2005) 11(7):144-152 Ho IA, Hui KM, Lam PY Glioma-specific and cell cycle regulated HSV-1 amplicon viral vector. Hum. Gene Ther. (2004) 15(5):495-508


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

LABORATORY OF GENE STRUCTURE AND EXPRESSION

Abnormal genetic make-up (aneuploidy) and enhanced survival are the hallmarks of cancer cells. Identification and characterization of genes / proteins involved in these mechanisms are important for diagnosis, prediction of treatment outcomes and development of anti-cancer drugs.

Aurora-A Kinase as an Anti-cancer Target

Senior Scientist PhD

cmrgop@nccs.com.sg

Cell cycle-dependent Sub-cellular localization of Aurora-A Kinase

RESEARCH STAFF Shen Kiat LIM (PhD)

DNA

A

Hong Lee HENG Yansong ZHU B

C

β-tubulin

Aurora-A

In recent years, Aurora-A expression has been emerging as a means to predict the outcome of the disease and Aurora-A as a promising anti-cancer target. As an important regulator of cell division with its oncogenic properties, Aurora-A is a potential target for inhibitory molecules that can inhibit cell cycle progression and thus can be a useful target for cancer therapy. Our research activities are directed towards understanding the negative regulation of Aurora-A kinase as well as Aurora-Alinked signaling pathways contributing towards tumorigenesis.

D

E

Subcellular localization of AKIP

Interphase

Ganesan GOPALAN

Aneuploidy, a condition referring to the loss or gain of chromosome or chromosomal regions, is one of the cellular changes associated with cancer. One of the mechanisms by which these defects occur is through abnormal chromosomal segregation during cell division. Recent discoveries show that the Aurora kinase protein family belongs to one such regulator of chromosome segregation. Aurora kinases evolve as a new family of mitotic, centrosome-and microtubule-associated kinases that regulate the structure and function of centrosomes and mitotic spindle. One of its members, Aurora-A kinase, has been shown to play a role in cancer. Higher levels of Aurora-A kinase have been found in a variety of human cancers such as those of colon, ovary, breast and pancreas.

AKIP

C23

DAPI

Merge DAPI

AKIP

Mitosis

F

Figure 1

AKIP

DAPI

Figure 2

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Negative Regulators of Aurora-A Laboratories worldwide are concentrating their efforts to isolate the negative regulators of Aurora-A protein with the ultimate aim of exploiting them for the effective treatment of cancer. In one such attempt, our team has isolated a novel negative regulator of AuroraA, named as AKIP (Aurora-A Kinase Interacting Protein). AKIP interacts specifically with Aurora-A and destabilizes it through proteosome-dependent yet ubiquitin-independent alternative protein degradation pathway. AKIP could therefore be a potentially useful target gene for anti-tumour drugs in Aurora-A over-expressing tumours.

SELECTED PUBLICATIONS Gopalan G, Chan CS, Donovan PJ A novel mammalian, mitotic spindle-associated kinase is related to yeast and fly chromosome segregation regulators. J. Cell Biol. (1997) 138:643-656. Gopalan G, Gilbert DJ, Copeland NG, Jenkins NA, Donovan PJ

Aurora-A oncogene as target for cancer treatment Inhibitors (AKIP) Ras

CANCER (breast, colon, gastric, liver neuroblastoma etc.) Progression

Aurora-A

p53

Estrogen

Chemoresistance (taxol, cisplatin, etoposide etc.)

Objectives: (i) To understand the normal and oncogenic signaling pathways of Aurora-A kinase

(ii) To identify as well as develop inhibitors that can down-regulate Aurora-A and thus facilitate better management of cancer

Chromosome localization of two new mammalian kinases related to yeast and fly chromosome segregation regulator. Mamm. Genome (1998) 9(1):86-87. Lim SK, Hui KM, Gopalan G Aurora-A interacting protein (AIP), a novel negative regulator of human Aurora-A kinase. J. Biol. Chem. (2002) 277(47):45558-45565. Lim SK, Gopalan G Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. Biochem. J. (2007) 403(1):119-127. Lim SK, Gopalan G Antizyme mediates AURKAIP1dependent degradation of Aurora-A. Oncogene (2007).

Aurora-A in Tumorigenesis & Chemoresistance Estrogen plays a major role in promoting the proliferation of both normal and neoplastic breast epithelium. However, studies on the identification of key molecules controlling cell proliferation and differentiation leading to breast cancer in ER-positive cells are still lacking. On the other hand, paclitaxel, a microtubule-interfering agent, has been widely used for both breast and ovarian cancer treatment. The extent of cancer cell death induced by paclitaxel is effectively reduced in the presence of estrogen. Paclitaxel-induced toxicity occurs through the activation of spindle checkpoint followed by metaphase arrest and apoptosis. Since over-expression of Aurora-A is implicated in both carcinogenesis and spindle checkpoint, we are interested in investigating if aurora-A is involved in estrogeninduced carcinogenesis and paclitaxel resistance. Simultaneously, we are studying the role of Aurora-A in Ras-induced tumorigenesis. Activated Ras is found in one third of human cancers. Aurora-A can cooperate with Ras and modify the Ras downstream effector RalA to promote transformation. In this area, our lab is interested in validating the importance of the Aurora-A-RalA interaction in Rasmediated tumorigenesis and developing peptide aptamers that can effectively disrupt the Aurora-A signalling and subsequently Ras-mediated tumorigenesis.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

CLINICAL TRIALS OFFICE

Joseph WEE Head, Division of Clinical Trials & Epidemiological Sciences FAMS, MBBS, FRCR

trdwts@nccs.com.sg

Cancer is a major disease worldwide. About 10 million people per year are diagnosed with the disease and 6 million die from it annually. Unfortunately, despite the best efforts, we are still unable to cure most patients with recurrent cancer. Hence, the search for new therapies is critical for the cure of cancer, and 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 efficacy and safety. The Clinical Trials Office provides the infra-structural support for the conduct of all phases of clinical trials at the National Cancer Centre Singapore (NCCS).

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

Research Experience Ai Lin LOW Senior Manager BSc (Pharm)(Hons)

ctelal@nccs.com.sg RESEARCH STAFF Noryati ABD RAHMAN Vera CHEN Catherine E.S.N. CHEOK Florencia M.H. GOH Su Mee HO Siew Lee HONG Fenny ISANTO Emily LIM Sheryl LIM Wen Ya ONG Jolin N. NING Valencia Agnes SHAH Yihui TAN Lan Ying WANG Shi Shin YANG Yi YANG Sarawati Bte ZAINOL ABIDIN

We have more than 14 years of experience in conducting clinical trials, and have completed more than 70 clinical trials involving close to 1,500 subjects in total. In addition, we have about 60 ongoing trials. Of particular interest, are trials using new synthetic drugs, vaccines and stem-cell mini-transplants on different cancers such as the breast, lung, nasopharynx, stomach, colorectum, liver and lymphomas. Our investigators have set aside time to run clinic sessions just for trial visits, in order to give ample time and attention to our trial subjects.

Our Infrastructure The NCCS has always supported its Institutional Review Board’s (IRB) commitment to protect human research subjects. Our IRB has obtained certification from the US Department of Health and Human Services in its Federal wide Assurance Programme for Human Subject Protection. This also qualifies the institution to perform US government supported research from the US National Cancer Institute. Our research coordinators are stringently selected to ensure that they have the aptitude, qualification and interests suitable for the work. Most of the coordinators are holders of a bachelors’ degree in medicine, nursing or the life / health sciences. The coordinators assist the investigators in logistical and administrative tasks, in study initiation, patient recruitment, trial conduct and data collection. NCCS has a modern IT infrastructure such as ISOFT which provides results of patients’ investigations; OAS for patients’ appointments / hospital stay and PACS for radio diagnostic images. We are also able to ensure that biological specimens for central laboratories are processed under the protocol prescribed conditions.

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

We work very closely with various other departments at the NCCS, such as the Pharmacy, Ambulatory Care Unit, Oncologic Imaging and the Pathology Laboratory at the Singapore General Hospital. O u r t r i a l d r u gs are stored in optimal conditions in the pharmacy. Dispensing, reconstitution and drug accountability are performed by registered oncology 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 protocol. The Department of Oncologic Imaging ensures that imaging requirements for trials are met and their radiologists provide image consultation service for trials upon request. We use the services of the Singapore General Hospital’s Pathology Laboratory, which is accredited by The College of American Pathologists; the Joint Commission International and certified by TÜV SÜD PSB Certification Pte Ltd. We have recently upgraded our Oracle Clinical data management system (for investigator initiated clinical trials) to manage data more efficiently so that accurate and ‘clean’ data can be extracted for statistical analysis. We have specific Standard Operating Procedures to help us achieve consistency in our clinical trials management processes, particularly in areas such as patient subject randomisation, blood processing and delivery, data management, ethics and regulatory requirements, safety reporting, other trial procedures and financial management.

Future Direction We aim to continue to act as the central liaison and to provide a centralised service in trial negotiation and conduct for the NCCS. We will continue to provide strong support to our doctors for both industry and investigator-initiated trials.

SELECTED PUBLICATIONS Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang ETL, Lee KM, Fong KW, Khoo-Tan HS, Lee KS, Loong S, Sethi VJ, Chua EJ, Machin D Randomised phase III trial of radiotherapy versus concurrent chemo-radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage III and IV nasopharyngeal cancer of the endemic variety. J. Clin. Oncol. (2005) 23(27):6730-6738. Tan EH, Szcesna A, Krzakowski M, Macha HN, Gatzemeier U, Mattson K, Wernli M, Reiterer P, Hui R, Von Pawel J, Bertetto O, Pouget JC, Burillon JP, Parlier Y, Abratt R Randomised study of vinorelbinegemcitabine versus vinorelbinecarboplatin in patients with advanced non-small cell lung cancer. Lung Cancer (2005) 49(2):233-240. Soo KC, Tan EH, Wee J Lim D, Tai BC, Khoo M, Goh C, Leong SS, Tan T, Fong KW, Lu P, See A, Machin D. Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison. Br. J. Cancer (2005) 93(3):279-286. Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, Sukin M, Van Kooten M, Dediu M, Findlay B, Tu Donsheng, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L A randomised phase III trial of erlotinib (Tarceva, OSI774) as second line or third line treatment following chemotherapy in patients with advanced non-small cell lung cancer. A trial of the National Cancer Institute of Canada Clinical Trials Group. New Eng. J. Med. (2005) 353:123-132. Leong SS, Wee J, Tay MH, Toh CK, Tan SB, Thng CH, Foo KF, Lim WT, Tan T, Tan EH Paclitaxel, gemcitabine, and carboplatin in metastatic nasopharyngeal carcinoma: a phase II trial using triplet combination. Cancer (2005) 103:569–575.

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BIOSTATISTICS AND EPIDEMIOLOGY UNIT

Say Beng TAN Visiting Principal Biostatistician MA, MSc, PhD, CStat

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.

saybeng@cteru.com.sg Joint Appointments: Director, Clinical Trials & Epidemiology Research Unit Adjunct Associate Professor, Community Occupational & Family Medicine, NUS

Clinical trials are the gold standard for the evaluation of new treatment strategies. New treatments which have been painstakingly developed in laboratories and shown to be very promising in animal studies will not be adopted in clinical practice unless they have first been proven effective in clinical trials, which can be time consuming and costly. Hence, much effort should be put into designing clinical trials that are efficient, effective and ethical, in terms of duration, cost and number of patients treated, to yield sound and practical information to recommend final therapies into clinical practice. The design, monitoring and analysis of clinical trials involve the application of biostatistical techniques. While many such techniques have already been developed, only a relatively small number of these are routinely used in practice. A key reason is that many of these methods have not made the transition from the ‘statistical lab’ to the clinic. However, these methods may potentially help to improve all aspects of the clinical trial process, ultimately resulting in more accurate conclusions to be drawn on the usefulness of new treatments. This has important ethical implications as patients participate in clinical trials with the expectation that the information that they provide will be used in the most optimal way to benefit future patients and potentially themselves as well.

Fei GAO Senior Biostatistician

Research thus needs to be carried out to test and bring better biostatistical and clinical trial methodologies into clinical practice. Epidemiological research endeavours to establish risk factors and patterns of disease in human populations (see figure 1).

MSc, PhD, CStat

ctegfe@nccs.com.sg

David MACHIN (PhD)

Hazard rate

STATISTICAL CONSULTANT

RESEARCH STAFF Huihua LI (PhD) Tam Cam HA (PhD) Siew Wan HEE Sze Huey TAN

Time since surgery (year)

Figure 1

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

SELECTED PUBLICATIONS Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam A, Tan EH Never-smokers with lung cancer: epidemiological evidence of a distinct disease entity. J. Clin. Oncol. (2006) 24(15):2245-2251. Low JS, Chua ET, Gao F, Wee JT Stereotactic radiosurgery plus intracavitary irradiation in the salvage of nasopharyngeal carcinoma. Head and Neck (2006) 28:321-329.

In Singapore, lifestyle patterns which mimic their Western counterparts such as dietary and reproductive changes may be linked to the increase in cancer incidence observed. Furthermore, there is a move towards establishing patient specific factors, including molecular biomarkers, which may provide a better treatment outcome for the patients. The design and conduct of scientifically sound epidemiological studies is important in ensuring quality results for the future benefit of all patients. Cancer is commonly thought to be caused by a multitude of factors, including environmental, lifestyle and genetic factors. Our unit has begun investigating various aspects of genetic epidemiology, where we focus on studying gene-environment interactions. In particular, we will examine those cancers that are of unique importance in Asian populations, namely female breast cancer, liver cancer and stomach cancer.

Ha TC, Lyons-Wall PM, Moore DE, Tattam BN, Boyages J, Ung OA, Taylor RJ Phytoestrogens and Indicators of Breast Cancer Prognosis. Nutrition and Cancer (2006) 56:3-10. Li H, Tai BC RNASEL gene polymorphisms and the risk of prostate cancer: a meta-analysis.

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 can have severe consequences on the interpretations of the research findings. This can eventually result in patients having less than optimal or even inappropriate treatment.

Clin Cancer Res. (2006) 12:5713-5719.

Moreover, there are many problems in medical research for which better (albeit less well known) statistical methods can 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.

A Bayesian dose finding design for dual endpoint Phase I trials.

The role of the Biostatistics and Epidemiology Unit is to engage in both areas of research, as well as to ensure that good quality biostatistics support is provided for all clinical trials and research studies conducted at the National Cancer Centre Singapore.

Loke YC, Tan SB, Cai Y, Machin D

Stat. Med. (2006) 25:3-22. Gao F, Nordin P, Krantz I, Chia KS, Machin D Variation in the seasonal diagnosis of acute lymphoblastic leukaemia: Evidence from Singapore, USA and Sweden. Am. J. Epidemiol. (2005) 162:753-763.

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Lab Programmes


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

WEE KIM WEE LABORATORY OF SURGICAL ONCOLOGY

Our Laboratory aims to individualize cancer therapeutics by integrating basic biology with translational research in head and neck cancers, and using the appropriate platforms to: (i)

Identify and understand the genes or factors involved in the cell-death pathways &

(ii)

Identify genetic determinants and potential biomarkers that can direct cancer therapy in future

N Gopalakrishna IYER Associate Investigator MBBS (Hons), PhD (Cambridge), MRCS (Edin)

narayanan.gopalakrishna.iyer@ nccs.com.sg

RESEARCH STAFF Hui Sun LEONG Chuan Bian LIM

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. Moreover, these same changes can also confer selective resistance to conventional methods of killing cancer cells, which utilise chemotherapy and radiotherapy to activate normally functioning death pathways within the cell. As these genetic changes may exist in various permutations, it is believed that the future of cancer therapy is in individualizing treatment to the genetic profile of each tumour, in each patient. In our laboratory, we have taken a two-pronged approach to deal with this issue. The first involves basic biological techniques aimed at identifying novel, hitherto uncharacterised pathways that modify cellular response to chemo- and radiotherapy. The second 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. One of the key mediators of this pathway is p53. 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. Our lab has focused on a group of proteins that have previously been shown to function as oncogenes. The KLF family of proteins has an important role in cellular transformation, and several members have been implicated in the control of apoptosis. We have identified KLF5 as an important modulator of cell death, which appears to function even in the absence of p53. Using cellular models we hope to identify mechanisms through which these proteins function, and use these pathways to promote cell death in a p53-independent manner. We eventually aim to interrogate whether other members of this family also play a role in p53-independent death pathways.

Lab Programmes

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Genetic Progression of Head and Neck Cancers Normal mucosa

Hyperplasia

No alterations

Mild/mod dysplasia

9p21 (p16) 3p

Severe dysplasia

17p13 (p53)

Sq cell carcinoma

11q13 (CCND1) 4q, 6p, 8p, 13q, 14q

Molecular Profiling of Head and Neck Cancers Head and neck cancers (HNC) 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 5 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. They thus require more precise diagnostic and prognostic tools to permit individualized treatment. Our approach to dissecting the heterogeneity of HNCs is based on several key prerequisites that few other institutions can match: 1) Tissue repositories, collecting a spectrum of clinical material; 2) Clinical databases; and 3) Easy access to technology, which in our cases involves established Affymetrix based microarray profiling techniques. Using these platforms, we intend to identify genetic determinants and potential biomarkers that can direct future therapy. These have been divided in several wellestablished clinical scenarios: 1) Progression from dysplasia to frank carcinomas; 2) Recurrence of early oral cancers; 3) Comparing classical versus young oral cancers; and 4) Hypopharyngeal 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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Lab Programmes

SELECTED PUBLICATIONS 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 (in press, 2007). Iyer NG, Chin SF, Daigo Y, Bannister A, Ozdag H, Kouzarides T, Aparicio S, Caldas C p300 is required for orderly G1/S transition in human cancer cells. Oncogene (2007) 26(1):21-29 Bundy 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. Iyer NG, Ozdag H, Caldas C p300/CBP and cancer. Oncogene (2004) 23(24):4225-4231. *Co-first author.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

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 KK Women and Children’s Hospital. It also provides visiting consultant services to hospice organizations in the community.

Cynthia GOH Senior Consultant & Head, Department of Palliative Medicine PhD, FAMS, FRCPE, FRCP, FAChPM

dpmgoh@nccs.com.sg

RESEARCH STAFF Grace PANG (MBBS) Alethea YEE (MBBS) Yin Yee WONG Gim Yew NG

Our research interests include validation of quality of life instruments, 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: Validation of the English and Chinese Versions of the EQ-5D to measure Quality of Life in Cancer Patients Quality of life is an important outcome measure in cancer treatment and cancer clinical trials. Cancer treatment may extend survival time at the expense of quality of life for cancer patients. Conversely, survival time may be shortened while quality of life is maintained. From the patients’ point of view and for cost utility analysis, it is important to be able to measure quality-adjusted life-years in addition to quality of life. The EQ-5D is a quality of life measure that takes both these indices into account. Quality of life studies in cancer patients using the EQ-5D would greatly enhance the provision of cancer care by allowing sound decision-making that takes both survival time and quality of life into account. It will also facilitate the economic analysis of cancer treatments as quality-adjusted life-years is an important tool in cost utility studies. The English version of the EQ-5D has not been sufficiently validated in cancer patients and there is no formal large scale validation of the Chinese version of the EQ-5D. This study, which seeks to validate the English and the Chinese version of the EQ-5D in cancer patients and to look at the equivalence of different language versions, has now been completed. It was recently selected for presentation at the 2007 Lancet Asia Medical Forum as it had been rated “ Highly Commended” by the Lancet editorial team.

Lab Programmes

45


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Pharmacogenetics of Opioid Receptor Genes Nausea and vomiting is one of the commonest side effects of clinically important opioid drugs such as morphine and fentanyl, which are commonly used for pain relief. Opioid-related nausea and vomiting is a major cause of patient morbidity that may result in adverse patient outcomes as well as increasing the socioeconomic burden of care to the individual and the state. The routine prescription of antiemetics to all patients is undesirable as these drugs may themselves cause side effects. Single nucleotide polymorphisms (SNPs) are the commonest form of polymorphisms in the human genome. It is postulated that they may contribute to inter-individual variations in drug response. In collaboration with the Laboratory of Liver Cancer Functional Genomics and KK Women and Children’s Hospital, this project aims to correlate the SNPs in the mu-opioid receptor gene with the occurrence of opioid-related side effects to drugs. Being able to identify patients with a genetic predisposition to opioid-induced emesis, either to a particular opioid or all opioids, would allow the prophylactic administration of antiemetics or the usage of alternative opioids thus improving the quality of patient care.

SELECTED PUBLICATIONS: Cheung YB, Goh C, Thumboo J, Khoo KS, Wee J Quality of life scores differed according to mode of administration in a review of three major oncology questionnaires. J. Clin. Epidemiol. (2006) 59(2):185-191. 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.

Reviewing End of Life Care for Patients with Advanced End Stage Disease in the Singapore General Hospital (SGH)

Cheung YB, Lim C, Goh C, Thumboo J, Wee J

End of life care is an important but inadequately researched aspect of healthcare in Singapore. As 54.5% of all annual deaths in Singapore occur in government and government restructured hospitals, it is important to examine the needs of patients dying in hospital and their families so that we may better improve the quality of care delivered to our patients and their families.

Health Qual. Life Outcomes (2005) 3:37.

This study aims to look at the characteristics defining end of life care that patients receive in a major tertiary hospital such as SGH and the effects of the quality of this care on family bereavement.

Order effects: a randomised study of three major cancer-specific quality of life instruments.

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.

Response Shift in Quality of Life in Chinese Breast Cancer Patients The Food Drug Administration (FDA) has stated quality of life (QOL) as an important end point for clinical trials. A favorable QOL is one of the important requirements for approval of new anticancer drugs. QOL can be affected by adaptations to changes in their health at various stages of diagnosis and treatment. These adaptations can be reflected in the response shift, which refers to the changes in values, internal standards and life quality as perceived by patients. Breast cancer patients were chosen for study of response shift because of the long natural history of the disease. It is also the commonest cancer affecting women in Singapore. In collaboration with the National University of Singapore, the aim of this project is to assess Chinese breast cancer patients at different phases of their disease for response shift in QOL in order to see its effect on the measurement of outcomes in cancer care.

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Lab Programmes

Cheung YB, Ng GY, Wong LC, Koo WH, Tan EH, Tay MH, Lim D, Poon D, Goh C, Tan SB Measuring quality of life in Chinese cancer patients: a new version of the Functional Living Index for Cancer (Chinese). Ann. Acad. Med. Singapore (2003) 32(3):376-380.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

NATIONAL CANCER CENTRE Singapore – VAN ANDEL RESEARCH INSTITUTE TRANSLATIONAL RESEARCH LABORATORY Professor Teh is the Head of Cancer Genetics and the Head of Sequencing Core and Cytogenetics Core at the Van Andel Research Institute (VARI). He also holds Adjunct Professorships in Universities such as Baylor Medical College, Michigan Technological University and Grand Valley State University, USA, Nanjing University, China and Karolinska Institute, Sweden. Professor Teh has published extensively, and also sits on various Editorial Boards such as Cancer Research, International Journal of Oncology, the Journal of Endocrine Genetics and Current Cancer Therapy Reviews.

Bin Tean TEH MD, PhD

Distinguished Visiting Investigator

Teh.B.T@nccs.com.sg

He has recently been appointed as Distinguished Visiting Investigator to set up the NCCSVARI laboratory, which will serve as the bridge between basic science research and clinical medicine both at the National Cancer Centre Singapore (NCCS) and at VARI. The laboratory will use high-throughput genomic and proteomic platforms, bioinformatics and clinical correlation studies, and animal models of cancer. The latter are for studies of gene functions as well as for drug testing. Using the latest cutting-edge technologies, the laboratory will focus on genomic and proteomic studies of clinical materials such as cancer tissues, patient body fluid and correlate them with clinical information such as long-term follow-up, drug response and survival. The programme will establish close collaboration with clinicians at NCCS and other clinical centres nationally, regionally and internationally. 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.

Lab Programmes

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Pat h way s to Knowledge

Dr Caroline Lee’s laboratory works on elucidating the molecular pathways leading to hepatocellular carcinoma, one of the most prevalent cancers in the Asia Pacific region. Her work will lead to identifying individuals who are at high risk of developing this cancer and experiencing relapse.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Publications in FY2006

1. Boyle P, Ariyaratne MA, Barrington R, Bartelink H, Bartsch G, Berns A, de Valeriola D, Dinshaw KA, Eggermont AM, Gray N, Kakizoe T, Karki BS, Kaslar M, Kerr DJ, Khayat D, Khuhaprema T, Kim IH, Martin-Moreno J, McVie G, Park JG, Philip T, Ringborg U, Rodger A, Seffrin JR, Semiglazov V, Soo KC, Sun YT, Thomas R, Tursz T, Veronesi U, Wiestler O, Yoo KY, Zatonski W, Zhao P (2006) Tobacco: deadly in any form or disguise. Lancet 367(9524) : 1710-1712 (Impact factor:23.407)

2. Quek R, Lim ST, Tan EH (2006) Pneumoperitoneum following percutaneous lung biopsy. Lancet 368(9549) : 1794 (Impact factor:23.407)

3. Low WK, Toh ST, Wee J, Fook-Chong SM, Wang DY (2006) Sensorineural hearing loss after radiotherapy and chemoradiotherapy: a single, blinded, randomized study. J Clin Oncol 24(12) : 1904-1909 (Impact factor:11.81)

4. Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam A, Tan EH (2006) Never-smokers with lung cancer: epidemiological evidence of a distinct disease entity. J Clin Oncol 24(15) : 2245-2251 (Impact factor:11.81)

5. Toh HC, Teo M, Ong KW, Lee V, Chan E, Lee AS, Vathsala A (2006) Use of sirolimus for EpsteinBarr virus-positive smooth-muscle tumour. Lancet Oncol 7(11) : 955-957 (Impact factor:7.855)

6. Chia WK, Lim YL, Greaves MW, Ang P (2006) Toxic epidermal necrolysis in patient with breast cancer receiving letrozole. Lancet Oncol 7(2) : 184-185 (Impact factor:7.855)

7. Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, Sabapathy K (2006) c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ 14(2) : 218-29 (Impact factor:7.785)

8. Bundy JG, Iyer NG, Gentile MS, Hu DE, Kettunen M, Maia AT, Thorne NP, Brenton JD, Caldas C, Brindle KM (2006) Metabolic consequences of p300 gene deletion in human colon cancer cells. Cancer Res 66(15) : 7606-7614 (Impact factor:7.616)

9. Aggarwal A, Guo DL, Hoshida Y, Yuen ST, Chu KM, So S, Boussioutas A, Chen X, Bowtell D, Aburatani H, Leung SY, Tan P (2006) Topological and Functional Discovery in a Gene Co-expression Meta-Network of Gastric Cancer. Cancer Res 66(1) : 232-241 (Impact factor:7.616)

10. Ou K, Kesuma D, Ganesan K, Yu K, Soon SY, Lee SY, Goh XP, Hooi M, Chen W, Jikuya H, Ichikawa T, Kuyama H, Matsuo E, Nishimura O, Tan P (2006) Quantitative profiling of drug-associated proteomic alterations by combined 2-nitrobenzenesulfenyl chloride (NBS) isotope labeling and 2DE/MS identification. J Proteome Res 5(9) : 2194-2206 (Impact factor:6.901)

11. Leong CT, Ong CK, Tay SK, Huynh H (2006) Silencing expression of UO-44 (CUZD1) using small interfering RNA sensitizes human ovarian cancer cells to cisplatin in vitro. Oncogene 26(6) : 870-880 (Impact factor:6.872)

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, Tavare S, Ellis I, Brenton JD, Caldas C (2006) Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers. Oncogene 2006 Sep 25 : Epub ahead of print (Impact factor:6.872)

13. Iyer NG, Xian J, Chin SF, Bannister AJ, Daigo Y, Aparicio S, Kouzarides T, Caldas C (2006) p300 is required for orderly G1/S transition in human cancer cells. Oncogene 2006 Jul 31 : Epub ahead of print (Impact factor:6.872)

Publications in FY2006

49


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

14. Zhang DW, Jeang KT, Lee CGL (2006) P53 negatively regulates the expression of FAT10, a gene upregulated in various cancers. Oncogene 25(16) : 2318-2327 (Impact factor:6.872)

15. Siddique MM, Sabapathy K (2006) Trp53-dependent DNA-repair is affected by the codon 72 polymorphism. Oncogene 25(25) : 3489-3500 (Impact factor:6.872)

16. Phang BH, Sabapathy K (2006) The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models. Oncogene 2006 Nov 20 : Epub ahead of print (Impact factor:6.872)

17. Ong CK, Leong C, Tan PH, Van T, Huynh H (2006) The role of 5’ untranslated region in translational suppression of OKL38 mRNA in hepatocellular carcinoma. Oncogene 2006 Aug 21 : Epub ahead of print (Impact factor:6.872)

18. Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, Lee SC, Lim R, Zhou QY, Goh BC, Tan EH, Balram C (2006) Pharmacogenetics of OATP-C (SLC21A6) gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics 16(9) : 683-691 (Impact factor:5.882)

19. Ren J, Kan A, Leong SH, Ooi LL, Jeang KT, Chong SS, Kon OL, Lee CG (2006) Fat10 plays a role in the regulation of chromosomal stability. J Biol Chem 281(16) : 11413-11421 (Impact factor:5.854)

20. 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 (Impact factor:5.854)

21. Balram C, Jada SR, Lim DWT (2006) Correspondence re: Cecchin et al., Carboxylesterase isoform 2 mRNA expression in peripheral blood mononuclear cells is a predictive marker of the irinotecan to SN38 activation step in colorectal cancer patients. Clin Cancer Res 2005;11:6901-7. Clin Cancer Res 12(6) : 1942 (Impact factor:5.715)

22. 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 (Impact factor:5.715)

23. Huynh H, Soo KC, Chow PK, Panasci L, Tran E (2006) Xenografts of human hepatocellular carcinoma: a useful model for testing drugs. Clin Cancer Res 12(14 Pt 1) : 4306-4314 (Impact factor:5.715)

24. Yu K, Ganesan K, Miller LD, Tan P (2006) A modular analysis of breast cancer reveals a novel low-grade molecular signature in estrogen receptor-positive tumors. Clin Cancer Res 12(11 Pt 1) : 3288-3296 (Impact factor:5.715)

25. Lim DWT, Jada SR, Balram C (2006) Correspondence re: Cecchin E et al., Carboxylesterase Isoform 2 mRNA Expression in Peripheral Blood Mononuclear Cells is a Predictive Marker of the Irinotecan to SN38 Activation Step in Colorectal Cancer Patients. Clin Cancer Res 11 : 6901-6907 (Impact factor:5.715)

26. Lim SG, Wai CT, Lee YM, Dan YY, Sutedja DS, Wee A, Suresh S, Wu YJ, Machin D, Lim CC, Fock KM, Koay E, Bowden S, Locarnini S, Ishaque SM (2006) A randomized, placebo-controlled trial of thymosin-alpha1 and lymphoblastoid interferon for HBeAg-positive chronic hepatitis B. Antivir Ther 11(2) : 245-253 (Impact factor:5.286)

27. Lal S, Rao Jada S, Xiang X, Lim WT, Lee EJ, Balram C (2006) Pharmacogenetics of target genes across the warfarin pharmacological pathway. Clin Pharmacokinet 45(12) : 1189-1200 (Impact factor:5.195)

28. 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) : 138-46 (Impact factor:5.171)

29. Ty A, See SJ, Khoo JBK, Rao J, Wong MC (2006) Oligodendroglial tumor chemotherapy using “decreased-dose-intensity” PCV: a Singapore experience. Neurology 66(2) : 247249 (Impact factor:4.947)

30. Fong CL, Mok CL, Hui KM (2006) Intramuscular immunization with plasmid coexpressing tumour antigen and Flt-3L results in potent tumour regression. Gene Ther 13(3) : 245256 (Impact factor:4.836)

31. 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 (Impact factor:4.8)

32. Olivo M, Ali-Seyed M (2007) Apoptosis signalling mechanisms in human cancer cells induced by Calphostin-PDT.. Int J Oncol 30(3) : 537-48 (Impact factor:4.7)

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

33. Tong WM, Lee MK, Galendo D, Wang ZQ, Sabapathy K (2006) Aflatoxin-B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock-in) mice. Int J Cancer 23 Mar 2006 : Epub ahead of print (Impact factor:4.7)

34. Lai PS, Cheah PY, Kadam P, Chua CL, Lie DK, Li HH, Eu KW, Seow-Choen F, Lee AS (2006) Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas. Int J Cancer 119(5) : 1061-1066 (Impact factor:4.7)

35. Marcom PK, Isaacs C, Harris L, Wong ZW, Kommarreddy A, Novielli N, Mann G, Tao Y, Ellis MJ (2006) The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat 2006 Aug 8 : Epub ahead of print (Impact factor:4.643)

36. Wong NS, Kahn HJ, Zhang L, Oldfield S, Yang LY, Marks A, Trudeau ME (2006) Prognostic significance of circulating tumour cells enumerated after filtration enrichment in early and metastatic breast cancer patients. Breast Cancer Res Treat 99(1) : 63-69 (Impact factor:4.643)

37. Wang B, Wang B, Ngoi S, Wang J, Chong SS, Lee CG (2006) The promoter region of the MDR1 gene is largely invariant, but different single nucleotide polymorphism haplotypes affect MDR1 promoter activity differently in different cell lines. Mol Pharmacol 70(1) : 267-276 (Impact factor:4.612)

38. Chong VF, Zhou JY, Khoo JB, Chan KL, Huang J (2006) Correlation between MR imagingderived nasopharyngeal carcinoma tumor volume and TNM system. Int J Radiat Oncol Biol Phys 64(1) : 72-76 (Impact factor:4.556)

39. Kang KB * Wang TT, * Woon CT, * Cheah ES, * Moore XL, * Zhu C,, Wang TT. Woon CT, Cheah ES, Moore XL, Zhu C, Wong MC (2007) # Wang TT, # Woon CT, # Cheah ES, # Moore XL, # Zhu C, # Wang TT, # 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) : 888-96 (Impact factor:4.556)

40. 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-inman study.. Int J Radiat Oncol Biol Phys 67(3 : 786-92 (Impact factor:4.556)

41. 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 (Impact factor:4.398)

42. Deyrup AT, Lee VK, Hill CE, Cheuk W, Toh HC, Kesavan S, Chan EW, Weiss SW (2006) EpsteinBarr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol 30(1) : 75-82 (Impact factor:4.377)

43. Cao X, Eu KW, Kumarasinghe MP, Li H, Loi C, Cheah PY (2006) Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J Med Genet 43(3) : e13 (Impact factor:4.33)

44. Wong AS, Soo RA, Lu JJ, Loh KS, Tan KS, Hsieh WS, Shakespeare TP, Chua ET, Lim HL, Goh BC (2006) Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation in locally advanced nasopharyngeal carcinoma. Ann Oncol 17(7) : 1152-1157 (Impact factor:4.319)

45. Soo R, Wu J, Aggarwal A, Tao Q, Hsieh W, Putti T, Tan K, Soon W, Lai Y, Mow B, Hsu S, Loh K, Tan L, Tan P, Goh BC (2006) Celecoxib reduces microvessel density in patients treated with nasopharyngeal carcinoma and induces changes in gene expression.. Ann Oncol 17(11) : 1625-1630 (Impact factor:4.319)

46. Rodrigues F, Sarkar-Tyson M, Harding SV, Sim SH, Chua HH, Lin CH, Han X, Karuturi RK, Sung K, Yu K, Chen W, Atkins TP, Titball RW, Tan P (2006) A Global Map of Growth Regulated Gene Expression in Burkholderia pseudomallei, the Causative Agent of Melioidosis. J Bacteriol 2006 Sep 22 : Epub ahead of print (Impact factor:4.167)

47. Ihrlund LS, Hernlund E, Viktorsson K, Panaretakis T, Barna G, Sabapathy K, Linder S, Shoshan MC (2006) Two distinct steps of Bak regulation during apoptotic stress signaling: Different roles of MEKK1 and JNK1. Exp Cell Res 7 Mar 2006 : Epub ahead of print (Impact factor:4.148)

48. Soo KC, Wee J, Tan EH (2006) Reply: Surgery vs chemoRT for locally advanced operable head and neck cancers. Br J Cancer 94(10) : 1546-1547 (Impact factor:4.115)

Publications in FY2006

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

49. Krubasik D, Iyer NG, English WR, Ahmed AA, Vias M, Roskelley C, Brenton JD, Caldas C, Murphy G (2006) Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition. Br J Cancer 95(2) : 245 (Impact factor:4.115)

50. Wang Z, Sew PH, Ambrose H, Ryan S, Chong SS, Lee EJ, Lee CG (2006) Nucleotide sequence analyses of the MRP1 gene in four populations suggest negative selection on its coding region. BMC Genomics 7 : 111 (Impact factor:4.092)

51. Jaichandran S, Yap ST, Khoo AB, Ho LP, Tien SL, Kon OL (2006) In Vivo Liver Electroporation: Optimization and Demonstration of Therapeutic Efficacy. Hum Gene Ther 2 Feb 2006 : Epub ahead of print (Impact factor:4.079)

52. Wang GY, Ho IA, Sia KC, Miao L, Hui KM, Lam PY (2007) Engineering of an improved cell cycle regulatable HSV-1 amplicon vector with enhanced transgene expression in proliferating cells yet attenuated activities in resting cells. Hum Gene Ther Mar 2007 : Epub ahead of print (Impact factor:4.079)

53. Lim LC, Tan MH, Eng C, Teh BT, Rajasoorya RC (2006) Thymic carcinoid in multiple endocrine neoplasia 1: genotype-phenotype correlation and prevention. J Intern Med 259(4) : 428-432 (Impact factor:4.04)

54. 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[Epub] (Impact factor:4.026)

55. 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 (Impact factor:3.937)

56. Lee CI, Leong SH, Png AE, Choo KW, Syn C, Lim DT, Law HY, Kon OL (2006) An isothermal method for whole genome amplification of fresh and degraded DNA for comparative genomic hybridization, genotyping and mutation detection. DNA Res 13(2) : 77-88 (Impact factor:3.896)

57. Thong PSP, Olivo M, Kho KW, Harris M, Soo KC Laser Confocal Endomicroscopy as a Novel Technique for Fluorescence Diagnostic Imaging of the Oral Cavity. J Biomed Opt 12(1) : 014007 (Impact factor:3.557)

58. Yap KPL, Ang P, Lim IHK, Ho GH, Lee ASG (2006) Detection of a novel Alu-mediated BRCA1 exon 13 duplication in Chinese breast cancer patients and implications for genetic testing. Clin Genet 70(1) : 80-82 (Impact factor:3.276)

59. Thumboo J, Wee HL, Cheung YB, Machin D, Luo N, Fong KY (2006) Development of a Smiling Touchscreen multimedia program for HRQoL assessment in subjects with varying levels of literacy. Value Health 9(5) : 312-319 (Impact factor:3.211)

60. Zhou Y, Tang K, Law HY, Ng IS, Lee CGL, Chong SS (2006) FMR1 CGG repeat patterns and flanking haplotypes in three Asian populations and their relationship with repeat instability. Ann Hum Genet 70(Pt 6) : 784-796 (Impact factor:3.192)

61. Goh BK, Ooi LL, Tan YM, Cheow PC, Chung YF, Chow PK, Wong WK (2006) Clinico-pathological features of cystic pancreatic endocrine neoplasms and a comparison with their solid counterparts. Eur J Surg Oncol 32(5) : 553-556 (Impact factor:3.184)

62. 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 2007 Jan 30 : Epub ahead of print (Impact factor:3.172)

63. Ang BT, Wong J, Lee KK, Wang E, Ng I (2006) Temporal changes in cerebral tissue oxygenation with cerebrovascular pressure reactivity in severe traumatic brain injury. J Neurol Neurosurg Psychiatry 2006 Oct 6 : Epub ahead of print (Impact factor:3.122)

64. Chin WW, Lau W, Ramaswamy B, Heng PW, Olivo M (2006) 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) : 127-33 (Impact factor:3.049)

65. Du HY, Bay BH, Mahendran R, Olivo M (2006) Hypericin-mediated photodynamic therapy elicits differential interleukin-6 response in nasopharyngeal cancer. Cancer Lett 235(2) : 202-208 (Impact factor:3.049)

66. Pook SH, Toh CK, Mahendran R (2006) Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity. Cancer Lett 238(1) : 146-152 (Impact factor:3.049)

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Publications in FY2006


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

67. Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M, Williams BO, Teh BT (2006) Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Biochem Biophys Res Commun 350(1) : 17-24 (Impact factor:3)

68. Ho IA, Hui KM, Lam PY (2006) Targeting proliferating tumor cells via the transcriptional control of therapeutic genes. Cancer Gene Ther 13(1) : 44-52 (Impact factor:3)

69. Zhou Q, Bun Cheung Y, Rao Jada S, Teck Lim W, Kuo WL, Gray JW, Lee AS, Balram C (2006) EGFR Intron 1 Polymorphism in Asian Populations and its Correlation with EGFR Gene Expression and Amplification in Breast Tumor Tissues. Cancer Biol Ther 5(11) : 14451449 (Impact factor:2.981)

70. Manivasager V, Yee KK, Heng PW, Soo KC, Olivo M (2006) A study comparing endogenous protoporphyrin IX induced by 5-ALA and ALA-methyl ester with exogenous PpIX and PpIX dimethyl ester in photodynamic diagnosis of human nasopharyngeal carcinoma xenografts. Int J Oncol 29(4) : 997-1002 (Impact factor:2.681)

71. Lee AT, Lee CG (2007) Oncogenesis and transforming viruses: the hepatitis B virus and hepatocellularcarcinoma--the etiopathogenic link. Front Biosci 12 : 234-45 (Impact factor:2.623)

72. Gan SU, Kon OL, Calne RY (2006) Genetic engineering for haemophilia A. Expert Opin Biol Ther 6(10) : 1023-1030 (Impact factor:2.553)

73. Cheung YB, Goh C, Thumboo J, Khoo KS, Wee J (2006) Quality of life scores differed according to mode of administration in a review of three major oncology questionnaires. J Clin Epidemiol 59(2) : 185-191 (Impact factor:2.538)

74. 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 (Impact factor:2.459)

75. Ha TC * Lyons-Wall PM, * Moore DE, * Tattam BN, * Boyages J, * Ung OA, Ha TC., Lyons-Wall PM, Moore DE, Tattam BN, Boyages J, Ung OA, Taylor RJ (2006) Phytoestrogens and indicators of breast cancer prognosis.. Nutr Cancer 56(1) : 3-10 (Impact factor:2.426)

76. Nolan WP, Aung T, Machin D, Khaw PT, Johnson GJ, Seah SK, Foster PJ (2006) Detection of narrow angles and established angle closure in Chinese residents of Singapore: potential screening tests. Am J Ophthalmol 141(5) : 896-901 (Impact factor:2.393)

77. Quek R, Lim ST, Ong S (2006) Hepatocellular carcinoma--Pathological complete response to oral capecitabine, megestrol and thalidomide. Acta Oncol 45(1) : 95-97 (Impact factor:2.362)

78. Woo E, Tan BK, Koong HN, Yeo A, Chan MY, Song C (2006) Use of the extended V-Y latissimus dorsi myocutaneous flap for chest wall reconstruction in locally advanced breast cancer.. Ann Thorac Surg 82(2): : 752-755 (Impact factor:2.229)

79. Goh BK, Tan YM, Lin SE, Chow PK, Cheah FK, Ooi LL, Wong WK (2006) CT in the preoperative diagnosis of fish bone perforation of the gastrointestinal tract. Am J Roentgenol 187(3) : 710-714 (Impact factor:2.209)

80. Yu Y, Kim HS, Chua HH, Lin CH, Sim SH, Lin D, Derr A, Engels R, DeShazer D, Birren B, Nierman WC, Tan P (2006) Genomic patterns of pathogen evolution revealed by comparison of Burkholderia pseudomallei, the causative agent of melioidosis, to avirulent Burkholderia thailandensis. BMC Microbiol 6 : 46 (Impact factor:2.176)

81. Toh CK, Lim WT (2006) Lung cancer in never-smokers. J Clin Pathol 2006 Aug 17 : Epub ahead of print (Impact factor:2.17)

82. Chin WW, Heng PW, Bhuvaneswari R, Lau WK, Olivo M (2006) The potential application of chlorin e6-polyvinylpyrrolidone formulation in photodynamic therapy. Photochem Photobiol Sci 5(11) : 1031-1037 (Impact factor:2.147)

83. Saw CL, Olivo M, Soo KC, Heng PW (2006) Spectroscopic characterization and photobleaching kinetics of hypericin-N-methyl pyrrolidone formulations. Photochem Photobiol Sci 5(11) : 1018-1023 (Impact factor:2.147)

84. Low JS, Chua ET, Gao F, Wee JT (2006) Stereotactic radiosurgery plus intracavitary irradiation in the salvage of nasopharyngeal carcinoma. Head Neck 28(4) : 321-329 (Impact factor:1.975)

85. Tham IW, Lee KM, Yap SP, Loong SL (2006) Outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated with radiotherapy, with or without chemotherapy. Head Neck 28(2) : 126-134 (Impact factor:1.975)

Publications in FY2006

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

86. Goh BK, Tan YM, Cheow PC, Chung YF, Chow PK, Wong WK, Ooi LL (2006) Cystic lesions of the pancreas: an appraisal of an aggressive resectional policy adopted at a single institution during 15 years. Am J Surg 192(2) : 148-154 (Impact factor:1.924)

87. Goh BK, Tan HK (2006) Double pylorus. Am J Surg 191(4) : 515-516 (Impact factor:1.924)

88. Goh BK, Tan HK, Tan FL, Koong HN (2006) Epidural emphysema associated with spontaneous pneumomediastinum. Am J Surg 192(3) : 355-356 (Impact factor:1.924)

89. Goh BK, Tan YM, Chung YF, Chow PK, Ooi LL, Wong WK (2006) Retroperitoneal schwannoma. Am J Surg 192(1) : 14-18 (Impact factor:1.924)

90. Cheung YB, Daniel R, Ng GY (2006) Response and Non-response to a Quality-of-Life Question on Sexual Life: A Case Study of the Simple mean Imputation Method. Qual Life Res Epub ahead of print (Impact factor:1.915)

91. Ng KS, Tan AG, Chen KK, Wong SK, Tan HM (2006) CT features of primary epiploic appendagitis. Eur J Radiol Epub ahead of print (Impact factor:1.888)

92. 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) : 166-74 (Impact factor:1.886)

93. Hum AY, Tan AS, Goh CR, Ju CA (2006) Hospice awareness in Singapore.. Palliat Med 20(3) : 221 (Impact factor:1.861)

94. Goh BK, Koong HN (2006) Massive traumatic extrapleural hematoma mimicking hemothorax: a potential pitfall of penetrating chest trauma. J Trauma. 61(4) : 995-997 (Impact factor:1.722)

95. Goh BK, Tan YM, Yap WM, Wong CY (2006) Hemorrhage into a pancreatic lymphangioma after blunt trauma mimicking a post-traumatic pancreatic pseudocyst. J Trauma 61(4) : 992-994 (Impact factor:1.722)

96. Goh BK, Koong HN (2006) Non-operative management of idiopathic segmental infarction of the greater omentum successfully diagnosed by computed tomography. J Gastroenterol Hepatol 21(10) : 1638-1639 (Impact factor:1.718)

97. Goh BK, Teo MC, Chng SP, Tan HW, Koong HN (2006) Upper gastrointestinal bleed secondary to duodenal metastasis: a rare complication of primary lung cancer. J Gastroenterol Hepatol 21(2) : 486-487 (Impact factor:1.718)

98. Goh BK, Tan YM, Chan WH, Yap CK, Ong HS, Wong WK (2006) Intra-abdominal lymphangioma: usefulness of endoscopic ultrasound and laparoscopy in diagnosis. J Gastroenterol Hepatol 21(1 Pt 2): : 340-341 (Impact factor:1.718)

99. Goh BK, Tan YM, Ooi LL (2006) Hepatobiliary and pancreatic: Cystic lymphangioma of the pancreas. J Gastroenterol Hepatol 21(3) : 618 (Impact factor:1.718)

100. Sun YJ, Lee ASG, Wong SY, Paton NI (2006) Association of Mycobacterium tuberculosis Beijing genotype with tuberculosis relapse in Singapore. Epidemiol Infect 134(2) : 329332 (Impact factor:1.674) 101. Jada SR, Hamzah AS, Lajis NH, Saad MS, Stevens MF, Stanslas J (2006) Semisynthesis and cytotoxic activities of andrographolide analogues. J Enzyme Inhib Med Chem 21(2) : 145155 (Impact factor:1.667) 102. Low WK, Gopal K, Goh LK, Fong KW (2006) Cochlear implantation in postirradiated ears: outcomes and challenges. Laryngoscope 116(7) : 1258-1262 (Impact factor:1.617) 103. Goh BK, Tan YM, Yap WM, Cheow PC, Chow PK, Chung YF, Wong WK, Ooi LL (2006) Pancreatic serous oligocystic adenomas: clinicopathologic features and a comparison with serous microcystic adenomas and mucinous cystic neoplasms. World J Surg 30(8) : 1553-1559 (Impact factor:1.601) 104. Goh BK, Tan YM, Chung YF, Chow PK, Cheow PC, Wong WK, Ooi LL (2006) A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients.. World J Surg 30(12) : 236-45 (Impact factor:1.601) 105. Goh BK, Quah HM, Chow PK, Tan KY, Tay KH, Eu KW, Ooi LL, Wong WK (2006) Predictive factors of malignancy in adults with intussusception. World J Surg 30(7) : 1300-1304 (Impact factor:1.601) 106. Teo M, Foo KF, Koo WH, Wong LT, Soo KC (2006) Lessons Learned from Initial Experience with Peritonectomy and Intra-peritoneal Chemotherapy Infusion. World J Surg 2006 Sep 7 : Epub ahead of print (Impact factor:1.601)

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

107. Goh BK, Chow PK, Quah HM, Ong HS, Eu KW, Ooi LL, Wong WK (2006) Perforation of the gastrointestinal tract secondary to ingestion of foreign bodies. World J Surg 30(3) : 372377 (Impact factor:1.601) 108. Thong PSP, Watt F, Ren MQ, Tan PH, Soo KC, Olivo M (2006) Hypericin-photodynamic therapy (PDT) using an alternative treatment regime suitable for multi-fraction PDT. J Photochem Photobiol B 82(1) : 1-8 (Impact factor:1.597) 109. 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) : 207-18 (Impact factor:1.597) 110. Chin WW, Lau W, Heng PW, Ramaswamy B, Olivo M (2006) Fluorescence imaging and phototoxicity effects of new formulation of chlorin e6-polyvinylpyrrolidone. J Photochem Photobiol B Mar 20 : Epub ahead of print (Impact factor:1.597) 111. Saw CL, Olivo M, Chin WW, Soo KC, Heng PW (2006) 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 2006 Nov 27 : Epub ahead of print (Impact factor:1.597) 112. Chiu LQ, Lee DWS, Gao F, Ng GY, Toh CK (2006) Cancer patients’ preferences for communication of unfavorable news: an Asian perspective. Support Care Cancer 16 Feb 2006 : Epub ahead of print (Impact factor:1.59) 113. Chuah KL, Yap WM, Tan HW, Koong HN (2006) Recurrence of pulmonary acinic cell carcinoma. Arch Pathol Lab Med 130(7) : 932-933 (Impact factor:1.587) 114. Du HY, Li Y, Olivo M, Yip GW, Bay BH (2006) Differential up-regulation of metallothionein isoforms in well-differentiated nasopharyngeal cancer cells in vitro by photoactivated hypericin.. Oncol Rep 16(6) : 1397-402 (Impact factor:1.572) 115. 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 nonsmall cell lung cancer.. Oncol Rep 17(4) : 853-857 (Impact factor:1.572) 116. Goh BK, Ooi LL, Kumarasinghe MP, Tan YM, Cheow PC, Chow PK, Chung YF, Wong WK (2006) Clinicopathological Features of Patients with Concomitant Intraductal Papillary Mucinous Neoplasm of the Pancreas and Pancreatic Endocrine Neoplasm.. Pancreatology 6(6) : 520-526 (Impact factor:1.564) 117. Tan SB, Machin D (2006) Phase II trial designs in the presence of stratification. Stat Med 25(18) : 3220-3222 (Impact factor:1.477) 118. Tan SB, Machin D (2006) Bayesian two-stage designs for phase II clinical trials. Stat Med 25(19) : 3407-3408 (Impact factor:1.477) 119. Gao F, Chia KS, Krantz I, Nordin P, Machin D (2006) On the application of the von Mises distribution and angular regression methods to investigate the seasonality of disease onset. Stat Med 25(9) : 1593-1618 (Impact factor:1.477) 120. Loke YC, Tan SB, Cai Y, Machin D (2006) A Bayesian dose finding design for dual endpoint phase I trials. Stat Med 25(1) : 3-22 (Impact factor:1.477) 121. Pervaiz S, Olivo M (2006) Art and science of photodynamic therapy. Clin Exp Pharmcol P 33(5-6) : 551-556 (Impact factor:1.437) 122. Wong L, See HT, Khoo-Tan HS, Low JS, Ng WT, Low JJ (2006) Combined adjuvant cisplatin and ifosfamide chemotherapy and radiotherapy for malignant mixed mullerian tumors of the uterus. Int J Gynecol Cancer 16(3) : 1364-1369 (Impact factor:1.427) 123. See HT, Thomas DA, Bueso-Ramos C, Kavanagh J (2006) Secondary leukemia after treatment with paclitaxel and carboplatin in a patient with recurrent ovarian cancer. Int J Gynecol Cancer 16 Suppl 1 : 236-40 (Impact factor:1.427) 124. Tan CH, Chow PK, Thng CH, Chung AY, Wong WK (2006) Pancreatic adenocarcinoma that mimics groove pancreatitis: case report of a diagnostic dilemma. Digest Dis Sci 51(7) : 1294-1296 (Impact factor:1.388) 125. Tan KJ, Chow PK, Tan YM, Thng CH (2006) Portal vein thrombosis secondary to hyperhomocysteinemia: a case report. Digest Dis Sci 51(7) : 1218-1220 (Impact factor:1.388) 126. Goh BK, Tan YM, Kumarasinghe MP, Ooi LL (2006) Synchronous serous cystadenoma and pancreatic endocrine tumor: a case report and literature review. Digest Dis Sci 51(2) : 422-426 (Impact factor:1.388)

Publications in FY2006

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National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

127. 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) : 173-5 (Impact factor:1.388) 128. 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) : 374-80 (Impact factor:1.295) 129. Choo SP, Lim ST , Wong EH, Tao M (2006) Breast lymphoma: favorable prognosis after treatment with standard combination chemotherapy. Onkologie 29(1-2) : 14-18 (Impact factor:1.206) 130. Quek R, Ty A, Lim ST, See SJ, Wong MC, Yap SP, Sng I, Hee SW, Tao M (2006) Primary central nervous system lymphoma in an Asian population: a 15-year experience. Onkologie 29(10) : 455-459 (Impact factor:1.206) 131. Yoke PC, Tin GB, Kim MJ, Rajaseharan A, Ahmed S, Thongprasom K, Chaimusik M, Suresh S, Machin D, Bee WH, Seldrup J; Asian Lichen Planus Study Group (2006) A randomized controlled trial to compare steroid with cyclosporine for the topical treatment of oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102(1) : 47-55 (Impact factor:1.193) 132. Thong PSP, Watt F, Ren MQ, Soo KC, Olivo M (2006) Investigating the role of calcium and biological trace elements in hypericin photodynamic therapy induced tumor cell death using nuclear microscopy. Nuclear Instr and Meth B 231 : 315-320 (Impact factor:1.181) 133. Choo SP, Kong KH, Lim WT, Gao F, Chua K, Leong SS (2006) Electroacupuncture for refractory acute emesis caused by chemotherapy. J Altern Complement Med 12(10) : 963-9 (Impact factor:1.051) 134. Wu B, Wang M, Wang JG, Pan L, Hui KM (2006) Establishment of a discriminant mathematical model for diagnosis of deficiency-cold syndrome using gene expression profiling. J Altern Complement Med 12(8) : 751-761 (Impact factor:1.051) 135. Teo HE, Peh WC, Akhilesh M, Tan SB, Ishida T (2006) Congenital osteofibrous dysplasia associated with pseudoarthrosis of the tibia and fibula. Skeletal Radiol 2006 Aug 30 : Epub ahead of print (Impact factor:0.98) 136. Lee JS, Pei-Lin Ng P, Tao M, Lim WT (2006) Paraneoplastic pemphigus resembling linear IgA bullous dermatosis. Int J Dermatol 45(9) : 1093-1095 (Impact factor:0.942) 137. Goh BK, Ang P, Wu YJ, Goh CL (2006) Characteristics of basal cell carcinoma amongst Asians in Singapore and a comparison between completely and incompletely excised tumors. Int J Dermatol 45(5) : 561-564 (Impact factor:0.942) 138. 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 (Impact factor:0.895) 139. Teo MC, Tan YM, Hee SW, Chung YF, Chow KH, Cheow PC, Soo KC, Ooi PJ (2006) Metastectomy for non-colorectal, non-neuroendocrine liver secondaries. ANZ J Surg 76(7) : 575-578 (Impact factor:0.783) 140. Tan FL, Tan YM, Chung AY, Cheow PC, Chow PK, Ooi LL (2006) Factors affecting early mortality in spontaneous rupture of hepatocellular carcinoma. ANZ J Surg 76(6) : 448-452 (Impact factor:0.783) 141. Woon CY, Tan YM, Oei CL, Chung AY, Chow PK, Ooi LL (2006) Adult choledochal cysts: an audit of surgical management. ANZ J Surg 76(11) : 981-986 (Impact factor:0.783) 142. Goh BP, Tan YM, Chung YF, Chow PH, Ong HS, Lim DH, Wong WK, Ooi LP (2006) Non-neoplastic cystic and cystic-like lesions of the pancreas: may mimic pancreatic cystic neoplasms. ANZ J Surg 76(5) : 325-331 (Impact factor:0.783) 143. Tan EY, Hoon TP, Yong WS, Wong HB, Hui HG, Yeo AW, Wong CY (2006) Recurrent phyllodes tumours of the breast: pathological features and clinical implications. ANZ J Surg 76(6) : 476-480 (Impact factor:0.783) 144. Pan L, Wang M, Wang JG, Wu B, Hui KM (2006) Clinical and molecular evaluation of warming and tonic herb treatment for sibling patients of a typical kidney-yang deficiency family. Am J Chin Med. 34(3) : 387-400 (Impact factor:0.743) 145. Toh HC (2006), Public healthcare--welfare, market share or laissez-faire?--a Sentosa Carlsberg skytower view. Ann Acad Med Singapore 35(2) : 119-122 (Impact factor:0.419) 146. Low SC, Lo RH, Lau TN, Ooi LL, Ho CK, Tan BS, Chung AY, Koo WH, Chow PK (2006) Imageguided radiofrequency ablation of liver malignancies: experience at Singapore General Hospital.. Ann Acad Med Singapore 35(12) : 851-857 (Impact factor:0.419)

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Publications in FY2006


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

147. Ha TC, Tan SB, Soo KC (2006) The journal impact factor: too much of an impact?. Ann Acad Med Singapore 35(12) : 911-6 (Impact factor:0.419) 148. Lee VT, Chung AY, Chow PK, Thng CH, Low AS, Ooi LL, Wong WK (2006) Infected pancreatic necrosis--an evaluation of the timing and technique of necrosectomy in a Southeast Asian population. Ann Acad Med Singapore 35(8) : 523-530 (Impact factor:0.419) 149. Poon D, Foo KF, Chew L, Leong SS, Wee J, Tan EH (2006) Phase II Trial of Gemcitabine and Cisplatin Sequentially Administered in Asian Patients With Unresectable or Metastatic Non-small Cell Lung Cancer. Ann Acad Med Singapore 35(1) : 33-35 (Impact factor:0.419) 150. Tan FL, Tan YM, Heah SM, Seow-Choen F (2006) Adult Hirschsprung’s disease presenting as sigmoid volvulus: a case report and review of literature. Tech Coloproctol 10(3) : 245248 151. Chao VT, Lim DW, Tao M, Thirugnanam A, Koong HN, Lim CH (2006) Tracheobronchial obstruction as a result of mediastinal mass. Asian Cardiovasc Thorac Ann 14(2) : e17-18 152. Kah JCY, Sheppard CJR, Lee CGL, Olivo M (2006) Application of Antibody-Conjugated Gold Nanoparticles for Optical Molecular Imaging of Epithelial Carcinoma Cells. Proc SPIE 6095 : 1-6 153. 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) : 171-174 154. Wan WH, Tan KY, Ng C, Tay KH, Mancer K, Tay MH, Chia WK, Soo KC, Ooi LL (2006) Metastatic Malignant Phaeochromocytoma: A Rare Entity that Underlies a Therapeutic Quandary. Asian J Surg 29(4) : 294-302 155. Wee HL, Li SC, Xie F, Zhang XH, Luo N, Cheung YB, Machin D, Fong KY, Thumboo J (2006) Are Asians comfortable with discussing death in health valuation studies? A study in multi-ethnic Singapore.. Health Qual Life Outcomes 4 : 93 156. Sabapathy K (2006) Chapter 3 - Physiological role of the different JNKs – lessons from the JNK knockouts. JNK signaling; Edited by A. Lin. Landes BioSciences Chapter 3 : 29-39 157. Tan P (2006) Cancer therapy: molecular targets in tumor-host interactions. Singapore Med J 47(2) : 175-176 158. Zheng W, Olivo M, Kho KW, Thong P, Harris M, Soo KC (2006) Confocal fluorescence endomicroscopic imaging of the tongue. SPIE – Photonics West 5686 : 301-306 159. Seet E, Leong WL, Yeo AS, Fook-Chong S (2006) Effectiveness of 3-in-1 continuous femoral block of differing concentrations compared to patient controlled intravenous morphine for post total knee arthroplasty analgesia and knee rehabilitation. Anaesth Intensive Care 34(1) : 25-30 160. Olivo M, Chin W (2006) Perylenequinones in Photodynamic Therapy: Cellular versus Vascular Response. J Environ Pathol Toxicol Oncol 25(1-2) : 223-238 161. Chen HM, Tan WH, Tan WC, Yu CK, Lim TH, Tay MH, See HT (2006) Attitudes towards cancer survivors: a small survey. Singapore Med J. 47(2) : 143-146 162. Kho KW, Olivo M, Shen ZX, Soo KC (2006) Surface enhanced Raman spectroscopic (SERS) study of saliva in the early detection of oral cancer. SPIE-BIOS 5702 : 84-91 163. Lee SY, Sin YK, Kurup A, Agasthian T, Caleb MG (2006) Stent-graft for Recurrent Melioidosis Mycotic Aortic Aneurysm. Asian Cardiovasc Thorac Ann 14(2) : e38-40

Publications in FY2006

57


Healing Cancer with Light

This international multi-disciplinary team works on bringing research from the laboratory bench to the clinic by developing cutting-edge technologies that harness the power of light to diagnose and treat cancers.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

International Conferences

Speakers / Authors

Date

Title of Conference Abstract

Name & Location of Conference

Ho IA, Shim W, Chan K, Guo C, Wang GY, Cheang P, Hui KM, Lam YP

22 - 23 Mar 2007

Characterization of human bone marrow-derived mesenchymal stem cells before and after viral vectors infection.

3rd Annual Stem Cell Research & Therapeutics; San Diego, California, USA

Chen W, Salto-Tellez M, P Nallasivam, Ganesan K, Hou Q, Tan LK, Sii LH, Ito K, Tan B, Wu J, Tay A, Tan KC, Ang A, Tan BK, Tan PH, Ito Y, Tan P

31 Jan - 3 Feb 2007

Targets of Genome Copy Number Reduction in Primary Breast Cancers Identified by Integrative Genomics.

Oncogenomics 2007, Phoenix, Arizona, USA

Balram C, Jada SR, Goh BC, Lim R, Lim WT, Tan EH

10 -12 Nov 2006

The impact of UGT1A1*28 and UGT1A1*6 variants on irinotecan-induced neutropenia in Asian cancer patients receiving weekly and three-weekly irinotecan regimens.

18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; Prague, Czech Republic (2006)

Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Lee KM, Fong KW, Machin D

Nov-06

Final Report of SQNP01 – A Phase III Randomized Trial comparing RT with Chemo-RT for locally advanced Nasopharyngeal Cancer.

Proceedings of the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology; Philadelphia, USA (Oral Presentation)

Low JS, Toh CK, Fong KW, Chua ET, Tan TW, Leong SS, Tan EH, Wee JTS

Nov-06

Intensity Modulated Radiotherapy in the salvage of recurrent Nasopharyngeal Cancer.

Kam SY, Ling AM, Wong WK, Chan WH, Ong HS, Yap WM, Chau, Lai SH, Kon OL, Ho M

28 Oct - 1 Nov 2006

Proteomic Approaches for Biomarker Discovery in Gastric Cancer.

Human Proteome Organization 5th Annual World Congress; Long Beach, CA, USA

Tan MH, Chia KS, Ho GH, Tan SB, Gao F, Ang P

29 Sep - 3 Oct 2006

Evaluation of breast cancer risk factors based on the Singapore Breast Cancer Screening Project cohort.

31st European Society of Medical Oncology Congress; Istanbul, Turkey

Ang P, See HT, Ong WS, Ha TC, Tan PH

29 Sep - 3 Oct 2006

Axillary lymph node metastases in primary breast cancers 1 cm or smaller.

Tan LK, Yu K, Tan B, Soo KC, Wong CY, Yeo A, Ho GH, Koong HN, Yong WS, Yap K, Tan PH, Tan P

12 - 15 Sep 2006

Clinical Validation of Breast Cancer Gene Expression Signatures Using Customized Microarrays.

1st Annual AACR Conference on Molecular Diagnostics in Cancer Therapeutic Development; Chicago, USA

Wang Z, Wang J, Tantoso E, Tai AY, Chong SS, Lee CG

6 - 10 Aug 2006

Identification of Potentially Important Polymorphisms in the ABC Transporter Genes through their Genomic Signatures of Recent Positive Selection.

11th International Congress of Human Genetics; Brisbane, Australia

Lee CG

28 - 31 Aug 2006

Pharmacogenetics of the ABC drug transporters.

International Conference: Frontiers of Pharmacology and Toxicology; Chicago, Illinois, USA

Thong PSP, Olivo M, Kho KW, Manivasager V, Bhuvaneswari R, Soo KC

8 - 12 Jul 2006

Activation of the immune response against distant untreated lesion in recurrent angiosarcoma treated with photodynamic therapy.

The 33rd Meeting of the American Society for Photobiology and the Photostability of Drug and Drug Products Group; Rio Grande, Puerto Rico

International Conferences

59


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Speakers / Authors

Date

Title of Conference Abstract

Name & Location of Conference

Saw LL, Olivo M, Wohland T, Soo KC, Heng PW

8 - 12 Jul 2006

3D Confocal Microscopy and Real Time Uptake of Hypericin-N-Methyl Pyrrolidone Formulation Visualized in Human Bladder Carcinoma

The 33rd Meeting of the American Society for Photobiology and the Photostability of Drug and Drug Products Group; Rio Grande, Puerto Rico

Chin WW, Heng PW, Bhuvaneswari R, Dill O, Olivo M

8 - 12 Jul 2006

Investigation of antitumor efficacy using chlorin e6-polyvinylpyrrolidone in cancer models.

The 33rd Meeting of the American Society for Photobiology and the Photostability of Drug and Drug Products Group; Rio Grande, Puerto Rico

Bhuvaneswari R, Gan YY, Thong PS, Ho M, Soo KC, Olivo M

8 - 12 Jul 2006

Upregulation of Copper and Vascular Endothelial Growth Factor (VEGF) in Nasopharyngeal Carcinoma following Hypericin mediated Photodynamic Therapy (PDT).

The 33rd Meeting of the American Society for Photobiology and the Photostability of Drug and Drug Products Group; Rio Grande, Puerto Rico

Xiang XQ, Lal S, Chua J, Jada SR, Kong MC, Lee LH, Go ML, Balram C

28 - 30 Jun 2006

The influence of ApoE polymorphism on warfarin dose requirements in Asian population.

International Conference on Pharmacogenetics; Changsha, China

Yap Y, Kendall A, Banerji U, Walsh G, Smith IE

2 - 6 Jun 2006

Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer.

42nd Proceedings of the American Society of Clinical Oncology (ASCO) Meeting; Atlanta, Georgia

Wong NS, Gao F, Tan SB, Machin D

Confirmation of double-peaked time distribution of mortality for breast cacncer in a poplucation -based study.

Quek RH, Lim WT, Toh HC

Capecitabine and oxaliplatin (XELOX) in treatment of advanced gastric cancer

Jada SR, Xiang XQ, Zhou Q, Li HH, Ooi LL, Balram C

Hepatic expression of CYP3A4 and CYP3A5 genes in Asians and implications for pharmacokinetic variations during chemotherapy.

Chia J

How far are you willing to pay for the latest anticancer therapies? - poster presentation.

Balram C, Sparreboom A, Jada SR, Xiang XQ, Li HH, Mathijssen RH, van Schaik RH, Verweij J, Goh BC, Lim R, Tan EH

Pharmacogenetic influence of OATP1B1 variants *1b and *15 on irinotecan disposition in Asian and Caucasian cancer patients.

Lee AS, Cheah PY, Kadam P, Chua CLM, Lie DKH, Li HH, Eu KW, Seow-Choen F, Lai PS

31 May - 3 Jun 2006

Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas.

Human Genome Meeting (HGM2006) of the Human Genome Organisation, HUGO; Helsinki, Finland

Tran E, Soo KC, Chow PK, Huynh H

1 - 5 Apr 2006

Targeted inhibition of the MEK-ERK signaling cascade by the selective MEK1/2 inhibitor AZD6244 (ARRAY-142886) for the treatment of hepatocellular carcinoma.

97th American Association of Cancer Research (AACR) Scientific Meeting; Washington DC, USA

Toh HC, Sun L, Soe MY, Phoon YP, Teo M, Tan P

Effect of Granulocyte Colony-stimulating factor (G-CSF) mobilisation on the phenotypic properties and gene expression profile of T lymphocytes.

Kang KB, Wang TT, Woon CT, Cheah ST, Moore XL, Zhu CJ, Wong MC

Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib, leading to massive tumor necrosis and inhibition of angiogenesis.

Huynh H, Soo KC, Chow PK, Lawrence P, Tran E

Xenografts of human hepatocellular carcinoma: A useful model for testing drugs.

Broët P, Camilleri-Broët S, Zhang S, Tuefferd M, Alifano M, Wu Y, Régnard JF, Soong R, Lim E, Tan P

Genome-Wide Identification of Copy-Number Abnormalities in Early Stage Lung Cancer.

60

International Conferences


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Local Conferences

Speaker (s)

Date

Title of Conference Abstract

Location of Conference

Saw LLC, Olivo M, Wohland T, Fu CY, Soo KC, Heng WS

Sep-06

Effects of N-methyl pyrrolidone on cellular uptake of hypericin monitored by real-time 3D Confocal Microscopy.

Asian Pharmaceutics Graduate Congress – “The science of product design and pharmaceutical Technology”

Lal S, Chua J, Jada SR, Xiang XQ, Kong MC, Lee LH, Go ML, Balram C

21 - 22 Apr 2006

The effect of Apolipoprotein E isoforms on warfarin dose requirements in the Asian population.

SGH 15th Annual Scientific Meeting 2006

Jada SR, Xiang XQ, Lim R, Goh BC, Tan EH, Balram C

Dose dependent influence of SLCO1B1 diplotypes on irinotecan disposition in Asian cancer patients.

Tan X, Laa AT, Ren J, Sew PH, Lee CG

Characterisation of mutations in the Hepatitis B virus X gene in hepatocellular carcinoma patients in Singapore.

Ang P, Lim IH, Lee AS

Li-Fraumeni Syndrome in young onsent Breast cancer patients in Singapore.

Sia KC, Wang Y, Ho I, Miao L, Hui KM, Lam P

Study of liver specific promoter and its enhancer that is expressed specifically in liver cell lines for use in HSV-1 viral vector gene therapy.

Lee AS, Ang P

Genetic Testing of Hereditary Breast Cancer in Singapore.

Yeo A, Ngo L, Tay MH

Efficacy of Ketoconazole in refractory prostate cancer patients at the National Cancer Centre, Singapore.

Ang MK, Tao M, Quek R, Sng I, Lim ST

A special subset of MALT lymphoma with excellent prognosis.

Ang MK, Tao M, Quek R, Sng I, Lim ST

Spontaneous reversion of atrial fibrillation in a patient with cardiac lymphoma after chemotherapy.

Local Conferences

61


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Invited Lectures

Speaker (s)

Date

Title of Lectures / Seminars

Conference / Location of Lectures

Wee J

Dec-06

Gastric Cancer.

IAEA Nobel Prize Special Event for Asia and the Pacific; Bangkok, Thailand

Khoo JB

3 - 5 Nov 2006

Medical Imaging.

First Regional Combined Medical and Dental Conference; YWCA, Singapore

Ho M

27 - 28 Oct 2006

Update on the McLeod Mouse Model.

Third International Neuroacanthocytosis Symposium. Kyoto Prefectural University of Medicine; Kyoto, Japan

Tan P

22 - 24 Sep 2006

Genomic and Proteomic Discovery of Breast Cancer Biomarkers.

15th National Conference of the Indian Cooperative Oncology Network (ICON); Kerala, India

Tan P

20 - 22 Nov 2006

Application of Genomic Analyses in Gastric Cancer.

1st Asia-Pacific Gastric Cancer Conference; National University Hospital, Singapore

Wee J

Nov-06

Clinical Trials in NPC.

Royal Australian and New Zealand College Radiologists - Faculty of Radiation Oncology Meeting

Wee J

Nov-06

Metastatic NPC.

13th Hong Kong International Cancer Congress; Hong Kong

Olivo M

Nov-06

Photonics initiatives in novel cancer detection and photodynamic therapy.

Biopolis - Bioimaging seminar; Singapore

Lee ASG

12 Sep 2006

(1) Genetics, Genomics and Molecular Biology for the Nephrologist: The Basics. (2) Genetics, Genomics and Molecular Biology: Clinical Applications.

4th State-of-the-Art Nephrology Course (SOTANC); Singapore

Olivo M

Sep-06

Photonics initiatives in novel cancer detection and photodynamic therapy.

NTU and Northwestern University Collaboration

Wee J

Sep-06

Intensity Modulated Radio-Therapy.

Annual Scientific Meeting, Malaysian Oncological Society; Penang, Malaysia

Khoo JB

26 Jul 2005

Radiology of Head and Neck Cancers.

Head & Neck Course; SGH Postgraduate Medical Institute

Ong S

22 Jul 2006

Dilemmas in Internal Medicine.

3rd Annual Scientific Meeting; College of Physicians, Singapore

Wong NS

20 Jul 2006

Adjuvant Systemic Therapy for Breast Cancer.

Changi General Hospital

62

Invited Lectures


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Speaker (s)

Date

Title of Lectures / Seminars

Conference / Location of Lectures

Tan P

12 - 14 Jul 2006

Topological and functional discovery in a gene coexpression meta-network of gastric cancer.

Algorithmic Biology: Algorithmic Techniques in Computational Biology; National University of Singapore, Singapore

Wong NS

1-Jul-06

Cancer Screening and Prevention.

Public Talk, HDB Auditorium; Toa Payoh Central, Singapore

Ong S

10-Jun-06

AIA Cancer Education Talk.

AIA, Singapore

Olivo M

1-Jun-06

Novel Strategies in Cancer Detection and Therapy using Light-induced Drugs and Bio-optical Imaging.

18th Singapore Pharmacy Congress; Singapore

Ong S

25 - 27 May 2006

Management of Advanced Colorectal Cancer.

Hanoi and Ho Chi Min City, Vietnam

Tan P

22 - 23 May 2006

Metagenomics Across the Grid : Challenges and Opportunities.

GridAsia 2006; Singapore Management University, Singapore

Patrick Tan

14 - 19 May 2006

Stability and Noise in the Cancer Transcriptome.

2nd Sino-SMA Workshop on Computation and Systems Biology; Shanghai, China

Ong S

22 Apr 2006

AIA Cancer Education Talk.

AIA, Singapore

Wee J

Apr-06

Intensity Modulated Radio-Therapy.

International College of Surgeons Congress; Singapore

Invited Lectures

63


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Recognition

Prof Hui Kam Man

Ms Constance Saw

Dr Li Huihua

27-Mar-07

Sep-06

Aug-06

In recognition of outstanding contribution to research in SingHealth.

Effects of N-methyl pyrrolidone on cellular uptake of hypericin monitored by real-time 3D Confocal Microscopy.

Applied statistics in genetics and metaanalysis.

Best Poster Award

Singapore Millennium Foundation

GCEO Excellence in Research Award 2007 SingHealth Foundation

Asian Pharmaceutics Graduate Congress – “The science of product design and pharmaceutical Technology”

Ng Xin Yi, Asgarova Rana, Clarence Zhuang Boren, James Kah & A/Prof Malini Olivo

Dr Ong Choon Kiat

Mar-07

Aug-06

Development of Protein assay based on gold nanoparticles.

Regulation of a tumor suppressor, OKL38 gene in cancers.

Platinum Award: 1st Prize – Singapore Chemical Science Fair

Post-Doctoral Fellowship Award

National University of Singapore

Post-Doctoral Fellowship Award

Dr Ha Tam Cam Aug-06

Singapore Millennium Foundation

Epidemiology of cancer. Post-Doctoral Fellowship Award Singapore Millennium Foundation

Dr Gao Fei Aug-06 Epidemiology of cancer.

A/Prof Caroline Lee Oct-06

Aug-06

Cancer Genetics & Biology.

Chemotherapy of quiescent brain tumor stem cells.

SingHealth Foundation Investigator Excellence Award 2006

Post-Doctoral Fellowship Award

SingHealth Foundation

A/Prof Kanaga Sabapathy Oct-06 The molecular basis of human cancer – The role of the tumor-suppressor genes, p53 and p73 and the proto-oncogene, cJun, in regulating cellular life and death. SingHealth Foundation Post-doctoral Recruitment Award SingHealth Foundation

64

Dr Zhu Congju

Recognition

Singapore Millennium Foundation

Dr Lee Ming Kei Aug-06 Investigation of the roles of p53 in carcinogenesis by knock-in mouse models. Post-Doctoral Fellowship Award Singapore Millennium Foundation

Post-Doctoral Fellowship Award Singapore Millennium Foundation

Dr Ho Ai-Wei Ivy Aug-06 New strategies to enhance specific transgene expression that are targetted to glioma. Post-Doctoral Fellowship Award Singapore Millennium Foundation


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Dr Patricia Thong

Dr Tan Min-Han

Dr Kenneth Lee Ming Kei

Aug-06

Jun-06

Apr-06

Diagnosis & Treatment of Cancer using Novel Optical Imaging and Bio-photonics.

The von Hippel-Lindau gene mutation predicts for good prognosis in clear cell renal cell carcinoma.

Knock-in mouse models to study role of p53 mutation in HCC: analysis using hupki (human p53 knock-in) mice and ES cells harbouring mutant p53.

Post-Doctoral Fellowship Award Singapore Millennium Foundation

ASCO Foundation Merit Award American Society of Clinical Oncology

Dr Puan Kia Joo Aug-06 Human memory Vγ2Vδ 2 T cells and Nasopharyngeal Carcinoma. Post-Doctoral Fellowship Award Singapore Millennium Foundation

Dr Paula YP Lam To develop a Bioimaging system for tracking the migratory potential of AM-hMSCs towards tumor cells. Talent Development Fund

Mr Kho Kiang Wei The design of a SERS (Surface Enhanced Raman Spectroscope). Scholarship Award Singapore Millennium Foundation

Dr Tan Yu Meng

To Analyze the role of p73 in mitotic cell death. Scholarship Award Singapore Millennium Foundation

Mr Toh Wen Hong Apr-06 Relief of p53-mediated suppression of telomerase activation by p73. Duke Best Poster presentation – Winner – Basic Science category SingHealth, Annual Scientific Meeting, 2006, Singapore

Apr-06 Multiple Clinical Publications. SingHealth Excellent Publications Awards 2006

Dr Yong Wei Sean

SGH 15th Annual Scientific meeting

Sentinel node biopsy.

Mr Toh Wen Hong Aug-06

SingHealth, Annual Scientific Meeting, 2006, Singapore

Jun-06

SingHealth Foundation

Aug-06

Young Investigator’s award Finalist – Basic Science category

Dr Toh Chee Keong

2006 Department of Clinical – Research Grant #DCR/019/2006 Department of Clinical Research, SGH

Apr-06 Multiple Clinical Publications. SingHealth Excellent Publications Awards 2006 SGH 15th Annual Scientific meeting

Mr Ren Jianwei Aug-06 Molecular mechanisms in HCC development. Scholarship Award Singapore Millennium Foundation

Ms Tan Xueling (U of Melbourne AMS attachment Student) Apr-06 Characterisation of mutations in the Hepatitis B virus X gene in hepatocellular carcinoma patients in Singapore. Finalist, SGH Scientist Award (Oral) SGH 15th Annual Scientific Meeting

Recognition

65


M a i n ta i n i n g our Genome

Cancer, at its very core, is a genetic disease. A regulatory network of genes collectively known as the genome maintenance network (GMN), enables a human cell to sense and respond to different types of DNA-damaging agents (e.g. solar UV rays or toxic chemicals). Continued efforts in our laboratory aim to uncover aspects of how these pathways go awry and add to the understanding of what is now widely-held as the initiating and rate-limiting event in many forms of malignant growth.


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

International Collaborators

Principal Investigator / laboratory

International Collaborator(s)

Research Centre

Project Title

PROF HUI KAM MAN

Prof H Kim Lyerly Prof Walter Gunzburg

Duke Comprehensive Cancer Centre, USA Research Institute of Virology and Biomedicine, University of Veterinary Medicine; Vienna, Austria The Rayne Institute, King’s College, UK

Hepatocellular Carcinoma

Harvard Medical School, Massachusetts General Hospital-East, USA University of Zurich, Switzerland University of Toronto, Hospital for Sick Children Harvard Medical School, Massachusetts General Hospital-East, USA

Generation and characterization of chimeric viral vectors gene therapy for pre-clinical studies. Characterization of pYEBac102 recombinants Towards a better understanding of human gliomas

Department of Biological and Medical Research, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Initiation of strand incision at a G:T mismatch in model DNA by human cells: Characterization of a novel ATP-dependent pathway Triggering the calcium transient by non-ionizing (far UV) radiation Characterization of the prostaglandin E2-activated signaling pathway mediating the correction of RDS in ataxia telangiectasia fibroblasts Phosphoproteomic Identification of human tumor signalling susbtrates in vitro and in vivo: comparison with quiescent cells and normal tissues Radiobiological accuracy & uncertainty

Bek Chai Heah Laboratory of Cancer Genomics DR PAULA LAM Laboratory of Cancer Gene Therapy

PROF MALCOLM PATERSON Laboratory of Genome Maintenance

Prof Farzin Farzaneh Prof Xandra Breakefield A/Prof Fraefel C Prof Abhijit Guha Dr Bakhos A Tannous Dr Sibghat-Ullah Lari Dr Futwan A Al-Mohanna Dr Razmik Mirzayans Dr Brian J Druker

Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada Oregon Cancer Institute, Oregon Health Sciences University, Portland, Oregon, USA

Dr A Price Dr NACS Wong Dr H Monahan Dr DJ Harrison

Department of Oncology, University of Edinburgh, UK

A/PROF HUYNH The HUNG

Dr Samuel Freedman

Laboratory of Molecular Endocrinology

Dr Michael Pollak

Dr Mostafa Elhilali

Lady Davis Institute for Medical Research, McGill University, Canada Breast Cancer Prevention Centre, McGill University, Canada Translational Research Centre, McGill University, Canada Department of Medicine, McGill University, Canada McGill University, Canada

Dr Van Tan

Binh Dan Hospital, Viet Nam

Dr Khin Maung Win

Yangon General Hospital, Myanmar

Dr Gerald Batist Dr Laurence Panasci

Gene therapy of cancer

Department of Pathology, University of Edinburgh, UK Hormonal aspect of breast cancer Anti-estrogens in breast cancer treatment and preventation Chemo-preventation of breast and liver cancers Uses of SarCNU in the treatment of Hepatocellular Carcinoma IGF systems in bladder hypertrophy and bladder cancer Hepatitis B and C infection and liver cancer in Vietnam Insulin-like growth factor binding prolteins in HCC

International Collaborators

67


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

International Collaborator(s)

Research Centre

Project Title

A/Prof PATRICK TAN

University of Paris

Genomics of Lung Cancer

Laboratory of Molecular Genomics

Dr Phillippe Broet Dr Sophie Camilleri-Broët Dr Heike Grabsch

University of Leeds, UK

Molecular Genomics of Upper GI Cancers

DR KANAGA SABAPATHY

Dr Roger Reddel

Laboratory of Molecular Carcinogenesis

Dr Maria Sibilia

Children’s Hospital Research Centre, Melbourne, Australia University of Vienna, Austria

Dr Erwin Wagner

Institute of Molecular Pathology, Vienna, Austria

Dr Yoichi Taya

National Cancer Centre, Tokyo, Japan

Dr Saturo Kyo Dr Axel Behrens

Dept. of Obstetrics, University of Kobe, Japan University of Zurich, Switzerland & Imperial cancer Research Fund, UK University of Milan, Italy National Helenia Research Foundation, Athens, Greece Case Western Reserve University, Cleaveland, Ohio, USA Stanford University, USA Beckmann Centre, Stanford University, USA Pasteur Institute, France

Effects of telomerase on the longetivity and senescence of mouse primary cells Regulation of differentiation and embryonic development by p53 Role of p53 in ES cell differentiation Role of JNKs in development, growth and apoptosis Analysis of phosphorylation status of p53 and its effects on p53 regulation Telomerase promoter regulated tumor therapy Function of phosphorylation of c-Jun in T lymphocyte development and tumorigenesis Studies on p53/p73 Role of c-Jun/JNK in cellular signalling

Dr Massimo Broggini Prof Alex Pintzas Prof Robert Silverman Prof Stanley Cohen Dr Isabella Graef Dr Moshe Yaniv Dr Jonathan Weitzman Dr Fukunaga Rikiro Dr Karen Vousden Dr Luzia Fischer Dr Rene Bernards Dr Zhao Qi Wang

Roles of JNK-induced apoptosis Identification of upstream activators of p53 Role of NF-AT in JNK mediated fucntions in T cells Role of JNKs in regulation of p53/mdm2 & cell migration

Osaka University, Japan Beatson Institute, Glasgow, UK Polish Academy of Sciences Dutch Cancerer Institute (NKI) IARC, Lyon, France

Genetic screen to identify JNK targets Regulation of p73 Role of p53 polymorphism in Caucasian population Role of DUBs in rgualtion of p73 and cJun stability Mouse models for p53 & human cancer

Dr Peter J Donovan

University of California, Irvine, USA

Generation of Aurora-A knockout mice

Sir Roy Calne Dr Tai-Tung Yip Dr Sun Young Rha Dr Fan Hong & Dr Guo Qiang Crusade Laboratories Poetic Genetics, Inc.

Cambridge University, UK Ciphergen Biosystems Inc., USA Yonsei Cancer Center, Seoul, Korea. The First People’s Hospital of Yunnan, China Glasgow, Scotland, UK Burlingame, California, USA

Gene- & cell-based treatment of diabetes Protein profiling of gastric fluid Spectral karyotyping of gastric cancer cells Gastric fluid cytology and protein profiling Gene therapy vectors Site-specific recombination system

PROF SOO KHEE CHEE & A/PROF MALINI OLIVO

Prof Martin Harris

Melbourne University / Optiscan

Tan Chin Tuan Laboratory of Optical Imaging & Photodynamic Therapy

Prof Qian Peng

Dept of Pathology, The Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway Physicist, Laser-Forschungslabor, Urologische Klinik der LMU, Marchioninistr. 23, D-81377 Munich, FRG Wellman Labs of PhotoMedicine, Harvard Medical School, USA Haemato Science GmbH, Biotechnologiepark, 14943 Luckenwalde Germany University of Pennsylvania University College Hospital, London, UK & Ark Therapeutics, UK Plc University of Lund, Sweden

Endomicroscopy using fluorescent markers & 2-Photon Endoscopy Photobiology

DR GANESAN GOPALAN Laboratory of Gene Structure & Expression A/PROF KON OI LIAN Laboratory of Applied Human Genetics

Prof Baumgartner Prof Tayabba Hasan Dr Manfred Haupt Prof Britton Chance Prof Steven Bown Prof Sune Svanberg

68

International Collaborators

Biophotonics instrumentation in cancer diagnosis Photomedicine Fotolon (chlorin e6) as a pharmaceutical agent Biophotonics instrumentation in cancer diagnosis Photodynamic therapy Biophotonics instrumentation in cancer diagnosis


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

International Collaborator(s)

Research Centre

Project Title

PROF SOO KHEE CHEE & A/PROF MALINI OLIVO Tan Chin Tuan Laboratory of Optical Imaging & Photodynamic Therapy (cont’d)

Prof Sune Svanberg Dr Othmar Dill Prof Khin Maung Win

University of Lund, Sweden Serapeutics, Germany Dept of Heptology, Yangon General Hospital, Myanmar Dept of Clinical Oncology, Chinese University of Hong Kong

Biophotonics instrumentation in cancer diagnosis PDT and Immunology AHCC01

Prof Phillip Johnson A/Prof Thomas Leung Dr Tjakra Wibawa Manuaba Dr Thiravud Khuhaprema Prof Haron Ahmad A/Prof Michael Findlay Dr Si-Hyun Bae A/Prof Johnathan Cebon

A/PROF ANN LEE Laboratory of Molecular Oncology

Prof Joe Gray A/Prof Els Robanus-Maandag Prof Calvin Pang Dr Christina Rudduck-Sivaswaren Dr Nick Paton

A/PROF CAROLINE LEE

Dr Kuan-Teh Jeang

Laboratory of Liver Cancer Functional Genomics

Dr Linda Lee Dr Michael Gottesman

A/PROF LONDON LUCIEN OOI Laboratory of Liver Cancer Functional Genomics

Dr Llew Keltner Dr Jay Winship

Laboratory of Oncoproteomics

University of California, San Francisco, USA Centre for Human & Clinical Genetics, Leiden University Medical Centre (LUMC) Dept of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong Children’s Hospital at Westmead, Sydney Clinical Trials Unit, Medical Research Council, UK

Array CGH analysis of Cancer

National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA Johns Hopkins University School of Medicine, USA National Cancer Institute, National Institutes of Health, USA

Functional Genomics of HCC

LightSciences Corporation, USA

LSC-OL004 - A phase 1/2 open-label study to evaluate safety and prelimninary evidence of LED in the treatment of subjects with inoperable HCC A Phase 3 Randomized Study to Evaluate Survival of Patients Treated with Talaporfin Sodium (LS11) and Interstitial Light Emitting Diodes (LED) as Compared to the Standard of Care Therapies in the Treatment of Unresectable Hepatocellular Carcinoma (HCC)

University College Hospital, London, UK & Ark Therapeutics, UK Plc

Trial on EO-impregnated wound dressings

Massachusetts General Hospital-East, Harvard Medical School, USA The Jackson Laboratory, USA Children’s Hospital, Harvard Medical School, USA The Wellcome Trust Centre, Oxford, UK New York Blood Center, NY, USA

Proteomic Analysis of Dysferlinopathy

Dr James Chen

Dr Sy-Shi Wang Dr Stephen Barker DR MAC HO MENG FATT

Dept of Surgery, School of Medicine, University of Undayana, Bali, Indonesia National Cancer Institute, Bangkok, Thailand Dept of Surgery, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia Wellington Regional Oncology Unit, Wellington St Vincent’s Hospital, Catholic University of Korea, South Korea Austin and Repatriation Medical Centre, Melbourne, Australia

Dr Robert H Brown Jr Dr Gregory A Cox Dr Hart GW Lidov Prof Anthony P Monaco Dr Soohee Lee Dr Colvin Redman Dr Adrian Danek Dr Heike Grabsch

Munich, Germany Leeds University, UK

Mutational spectrum of BRCA 1 and BRCA2 genes in breast cancer FISH and array CGH analysis of cancer Molecular analysis of Mycobacterium tuberculosis

Genetics of ABC transporters

Neuroacanthocytosis syndromes

Proteomic Approaches for Biomarker Discovery in Gastric Cancer

International Collaborators

69


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

International Collaborator(s)

Research Centre

Project Title

DR BALRAM CHOWBAY

Dr Alex Sparreboom

National Institutes of Health, USA

Laboratory of Clinical Pharmacology

Dr Howard McLeod

Washington University in St Louis School of Medicine, USA Institute Claudius Regaud, France Queensland Univ of Technology

Pharmacokinetics & pharmacogenetics in cancer therapy Pharmacogenetics in cancer patients

Dr Etienne Chatelut Dr Zhou Shufeng DR JOSEPH WEE Head, Division of Clinical Trials & Epidemiological Sciences

Dr Winnie Yeo Dr Anthony Chan Dr Alex Chang Dr Tony Mok Dr Benny Zee Dr Hyun Cheol Chung Dr Pun Hui Dr Lisa Horvath Dr Hei Cheul Jeung Dr Brigette Ma Dr Michael Millward Dr Michael Boyer Dr Sun Young Rha Dr Jae Kjung Roh Dr Qian Tao Dr Simon Chung Ho Yu Dr Ka-Fai To Dr Brigette Ma Dr Tony Mok Dr Michael Boyer Dr Anthony Chan Dr Alex Chang Dr Stephan Clarke Dr KC Lam Dr Ann D King Dr Anil T Ahuja Dr Benny Zee

70

International Collaborators

Dept of Clinical Oncology, Chinese University of Hong Kong Johns Hopkins Singapore Int Med Centre Dept of Clinical Oncology, Chinese University of Hong Kong Division of Haematology-Oncology, Yonsei Cancer Centre, Yonsei University College of Medicine. Dept of Clinical Oncology, Chinese University of Hong Kong Sydney Cancer Centre, Royal Prince Alfred Hospital Yonsei Metastasis Research, Yonsei Cancer Centre Dept of Clinical Oncology, Chinese University of Hong Kong School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital Sydney Cancer Centre, Royal Prince Alfred Hospital Division of Haematology-Oncology, Yonsei Cancer Centre, Yonsei University College of Medicine. Division of Haematology-Oncology, Yonsei Cancer Centre, Yonsei University College of Medicine. Cancer Epigenetics Lab, Dept of Clinical Oncology, Chinese University Of Hong Kong Dept of Diagnostic Radiology and Organ Imaging, Chinese University of Hong Kong Dept of Anatomical and Cellular Pathology, Chinese University of Hong Kong Dept of Clinical Oncology, Chinese University of Hong Kong Sydney Cancer Centre, Royal Prince Alfred Hospital Dept of Clinical Oncology, Chinese University of Hong Kong Johns Hopkins Singapore Int Med Centre Sydney Cancer Centre, Royal Prince Alfred Hospital Dept of Clinical Oncology, Chinese University of Hong Kong Dept of Diagnostic Radiology and Organ Imaging, Chinese University of Hong Kong Dept of Clinical Oncology, Chinese University of Hong Kong

Pharmacokinetics Pharmacokinetics & pharmacogenetics in cancer therapy A Phase I /II study of PXD101 in patients with unresectable hepatocellular carcinoma with pharmacokinetic and pharmacodynamic evaluation

A phase II study of triapine and gemcitabine as second-line treatment of advanced non-small cell lung cancer in patients who had prior gemcitabine with evaluation of the effect of triapine on gemcitabine pharmacokinetics and cellular uptake in peripheral mononuclear cells


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

International Collaborator(s)

Research Centre

Project Title

DR JOSEPH WEE

Dr Richard Ambinder

Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins Cancer Research, Baltimore Dept of Clinical Oncology, Chinese University of Hong Kong Johns Hopkins Singapore Int Med Centre Dept of Clinical Oncology, Chinese University of Hong Kong

A Phase I trial of 5- Azacitidine and Suberoylanilide hydroxamic acid in patients with Metastatic or Locally Recurrent Nasopharyngeal Carcinoma and Nasal NK-T cell Lymphoma

Head, Division of Clinical Trials & Epidemiological Sciences (cont’d)

Dr Anthony Chan Dr Alex Chang Dr Brigette Ma Dr Edwin Hui Dr Qian Tao Dr Steve Gore Dr Michael Carducci Dr Elizabeth Garrett-Mayer

DR TAN SAY BENG

Cancer Epigenetics Lab, Dept of Clinical Oncology, Chinese University Of Hong Kong Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins Cancer Research, Baltimore Johns Hopkins School of Medicine, Dept of Oncology, Division of Biostatistics, Baltimore University of Sheffield, UK

Visiting Principal Biostatistician

Dr Steven Julious Prof Mike Campbell Prof Peter Fayers

DR GAO FEI

Prof David Machin

United Kingdom Children’s Cancer Study Group, University of Leicester, UK

Senior Biostatistician

University of Aberdeen, UK

Early phase clinical trials Clinical Trial Designs Quality of Life Studies Double-peaked mortality risk following mastectomy for breast cancer in Singaporean women: Confirmation of findings from other regions

Prof David Machin

Kernel smoothing methods

Prof David Machin

Seasonality of lymphomes

Prof David Machin

On the evidence for seasonal variation in the onset of acute lymphoblastic leukaemia (ALL)

Dr Rubert Jakes

Department of Public Health and Primary Care, University of Cambridge, UK

Follow-up of the Singapore Breast Screening Project: Efficacy, Disease Progression and Mammographic Density

Dr Cheung Yin Bun

London School of Hygiene and Tropical Medicine, University of London, UK

Quality of Life research

Prof Mini Yu

Norris Comprehensive Cancer Center, University of Southern California, USA

Dietary and Genetic Determinants of Mammographic Density

Prof David Machin

United Kingdom Children’s Cancer Study Group, University of Leicester, UK

Phase II oncology trials with time-to-event endpoints

DR HA TAM CAM

Prof David Machin

University of Leicester, UK

Oral Lichen Planus and Squamous Cell Carcinoma

Epidemiologist

Dr Nguyen Ky-Anh

Biochemistry and Molecular Biology, University of Georgia, Georgia, USA

Ms Hee Siew Wan Biostatistician

International Collaborators

71


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Local Collaborators

Principal Investigator / laboratory

Local Collaborator(s)

Research Centre

Project Title

PROF HUI KAM MAN

Dr Tay Kiang Hiong Dr Linn Yeh Ching Dr Chang Guo Ming Dr Christopher Goh A/Prof London Lucien Ooi Dr Ho TH Dr John Low Dr Tan Eng Huat Dr Thomas Gong Dr Philip Eng Dr Ann Hsu A/Prof Philip Cheang

Dept of Diagnostic Radiology, SGH Dept of Haematology, SGH Dept of Orthopaedic Surgery, SingHealth Dept of Otolaryngology, SGH Dept of Surgical Oncology, NCCS KK Women’s & Children’s Hospital Dept of Radiation Oncology, NCCS Dept of Medical Oncology, NCCS National Technological University Respiratory & Critical Care Medicine, SGH

Rat as a model system for heart disease Immunotherapy of leukemia Stem cell research Nasopharyngeal cancer pathogenesis Hepatocellular pathogenesis Gene Expression of ovarian and cervical cancer Nasopharyngeal carcinoma Lung Cancer Diagnostic Imaging Lung Cancer Lung cancer genetics Nanoparticles for gene delivery

Dr Ng Wai Hoe Dr Winston Shim

Department of Neurosurgery, NNI National Heart Centre

Gene therapy of gliomas Stem cell research

DR GANESAN GOPALAN

Dr Balram Chowbay

Lab of Clinical Pharmacology, NCCS

Laboratory of Gene Structure & Expression

Dr Ho Gay Hui

Dept of Surgical Oncology, NCCS

Identification of functional polymorphisms in Aurora-A Epigenetic silencing of Ras-related and estrogenregulated growth inhibitor (RERG) expression in breast cancer progression

PROF MALCOLM PATERSON

Prof Barry Halliwell

Office of Life Sciences, NUS

Dr Xiao Zhi Cheng A/Prof London Lucien Ooi Dr Wong Chow Yin

Dept of Clinical Research, SGH Dept of Surgical Oncology, NCCS Dept of General Surgery, SGH

Dr Tan Puay Hoon

Dept of General Pathology, SGH

Dr Graeme Guy Dr Low Boon Chuan Dr Keli Ou

Institute of Molecular & Cell Biology Dept of Biological Sciences, NUS Proteomics Group, Agenica Pte Ltd

A/Prof Lee Seng Teik

Dept of Plastic Surgery, SGH

A/Prof Foo Keong Tatt Dr Christopher Cheng

Dept of Urology, SGH

Bek Chai Heah Laboratory of Cancer Genomics

DR PAULA LAM Laboratory of Cancer Gene Therapy

Laboratory of Genome Maintenance

A/PROF HUYNH THE HUNG Laboratory of Molecular Endocrinology

72

Local Collaborators

School of Materials Engineering, Nanyang Technological University

Relationship between aberrant calcium signaling and state of chronic oxidative stress in ataxia telangiectasia cells Role of ATM protein kinase in learning and memory Phosphoproteomic Identification of human tumor signalling susbtrates in vitro and in vivo: comparison with quiescent cells and normal tissues Use of phosphoErbB2 antibodies in molecular pathology Signal Transduction of Growth Factors Signal Transduction ICAT and mass spectrometry in functional proteomics The roles of phyto-chemicals in wound healing and breast, prostate and cervical cancer treatment Finasteride and anti-estrogen in treatment and preventation of prostate cancer


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

Local Collaborator(s)

Research Centre

Project Title

A/PROF HUYNH THE HUNG

Dr Tay Sun Kuie

Dept of Obstetrics & Gynaecology, SGH

Prof Soo Khee Chee Dr Goh Boon Cher Dr Tan Puay Hoon Dr Pierce Chow Dr Patrick Tan

National Cancer Centre Singapore National University Hospital Dept of Pathology, SGH Dept of General Surgery, SGH National Cancer Centre Singapore

Characterization of a novel tissue associated antigen for uterine and ovarian cancer Targeting of Insulin-like growth factor system in the treatment and early detection of hepatocellular carcinoma

Prof W.Y. Chan

Dept of Pharmacology, NUS

Dr Elaine Lim

National University of Singapore

A/Prof Hung Huynh A/Prof Manuel Salto Tellez Dr Richie Soong Dr Goh Boon Cher Dr Lee Soo Chin Dr Toh Han Chong Dr Tan Puay Hoon A/Prof Nallasivam Palanisamy Yoshiaki Ito Dr Yu Qiang

National Cancer Centre Singapore National University of Singapore

Laboratory of Molecular Endocrinology (cont’d)

A/PROF PATRICK TAN Laboratory of Molecular Genomics

A/PROF KANAGA SABAPATHY Laboratory of Molecular Carcinogenesis

A/PROF KON OI LIAN Laboratory of Applied Human Genetics

Gene expression profile in lung cancer cells treated with flavonoids Anti-angiogenesis in Cancer Treatment 1) Molecular Genetics of Lung Cancer 2) Genomics of Lung Cancer Primary Xenografts of HCC for Cancer Therapeutics

National University Hospital

Pharmacogenomics of Breast Cancer

National Cancer Centre Singapore Dept of Pathology, SGH Genome Institute of Singapore Institute of Molecular and Cell Biology Genome Institute of Singapore

Genomics of T-cell Response Molecular Genomics of Breast Cancer

A/Prof Uttam Surana Dr K Swaminathan Dr Matthew Whiteman A/Prof Alan Porter Dr Phan T Dr Xiao ZC Dr Li Baojie

Institute of Molecular & Cell Biology, NUS Dept of Biological Sciences, NUS Dept of Biochemistry, NUS Institute of Molecular & Cell Biology, NUS Dept of Surgery , NUS Dept of Clinical Research, SGH and IMCB Institute of Molecular & Cell Biology, NUS

Regulation of Differentiation and Cell Cycle Structural analysis of c-Jun & p73 Role of c-Jun pathway in apoptosis Role of JNKs in apoptosis Role of JNKs in epithelial/keratinocyte cell biology Role of JNKs in brain development Role of c-Abl & JNK in cellular signalling

Dr Patrick Tan Dr Mac Ho Meng Fatt Dr Toh Han Chong Dr Dennis T.H. Lim Dr Tan Soo Yong Dr Wong Wai Keong Dr Ong Hock Soo Dr Chan Weng Hooong Dr Priyanthi Kumarasinghe Dr Yap Wai Ming Dr Cora Chau Dr Pierce Chow Mr. Robert Ng Dr Ho Liam Pock Dr Tien Sim Leng Dr Lai Siang Hui Mr Choo Keng Wah Mr Steven Yap Dr Joel Lee Dr Nallasivam Palanisamy Dr Gerald Udolph Dr John Isaac

National Cancer Centre Singapore

1) Cancer Genomics & Genetics 2) Gene- & cell-based treatment of metabolic diseases

Singapore General Hospital

Health Sciences Authority Nanyang Polytechnic

Genome Inst of Singapore Institute of Bioengineering NUS Dept of Surgery

Local Collaborators

73


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

Local Collaborator(s)

Research Centre

Project Title

A/PROF KON OI LIAN

Cell Research Corporation Dr Li Guodong Dr Lim Sai Kiang Dr Tony Lim Dr Lai Siang Hui

c/o NUS NUMI, NUS GIS Singapore General Hospital Health Sciences Authority

Cell-based gene therapy Cell-based diabetes therapy

Fluorescence life-time imaging Nanotechnology

Prof YY Gan A/Prof Bay Boon Huat

Nanyang Technological University, IEEE Nanyang Technological University Nanyang Technological University, Dept of Materials Sciences Nanyang Technological University, NIE NUS, Anatomy

A/Prof Paul Heng

NUS Pharmacy

Prof Colin Sheppard

NUS Bioengineering Department

Prof Britton Chance Dr Weber Lau

SBIC Biopolis Department of Urology

Dr Chris Goh Dr Tan Puay Hoon Dr Kent Mancer Dr Sirajudeen

Dept of Otolaryngology, SGH Dept of Pathology, SGH

Prof Frank Watt

National University of Singapore, Dept of Physics

Prof Shen Ze Xiang Prof Seah Hock Soon A/Prof Lin Feng Dr Balram Chowbay Dr Thorsten Wohland

Nanyang Technological University, Mathematics & Physical Sciences Dean of Computer Engineering, NTU Computer Engineering, NTU CTE, National Cancer Centre Singapore National University of Singapore

Prof Dim-Lee Kwong A/Prof Poenar Daniel Puiu

Director, Institute of Microelectronics (IME) NTU, school of E&EE

Dr Peter Ang Dr Ho Gay Hui Dr Toh Han Chong Dr A. Vathsala Dr Eu Kong Weng Dr Cheah Peh Yean Dr Victor Lee Dr Chuah Khoon Leong Dr Tan Puay Hoon Mr. Lee Tze Chuen Dr Li Kuo Bin A/Prof Vincent Chow

Deparment of Medical Oncology, NCCS Department of Surgical Oncology, NCCS Deparment of Medical Oncology, NCCS Department of Renal Medicine, SGH Department of Colorectal Surgery

Mutation spectrum of BRCA1 and BRCA2

Department of Pathology, SGH

Molecular analysis of archived tumors

BioInformatics Institute

Computatonal analysis of mutations

Department of Microbiology, NUS

Molecular markers for breast cancer

Laboratory of Applied Human Genetics (cont’d)

Dr Christopher Syn PROF SOO KHEE CHEE & A/PROF MALINI OLIVO Tan Chin Tuan Laboratory of Optical Imaging & Photodynamic Therapy

A/PROF ANN LEE Laboratory of Molecular Oncology

74

Local Collaborators

Asst Prof Ng Beng Koon A/Prof. Subodh Mhaisalkar A/Prof Tim White

Nanyang Technological University, IEEE

Gastric cancer genomics/proteomics Gastric cancer genomics/proteomics; cell-based diabetes therapy Genomics

Molecular Photomechanisms In vivo Phosphodynamic Therapy of Hypericin & Hypocrellins New Formulations of Hypericin and Chlorin e6 as a photosensitizer Use of Gold Nanoparticles as a molecular specific agent for the prognosis of epithelial cancers in combination with in vivo optical imaging Biophotonics Fotolon mediated photodynamic therapy in bladder patients and in in vivo systems Endoscopy and 2 photon laser confocal fluorescence microscopy of early neoplasia in the oral cavity Ex vivo urine cytology using novel photosensitizer Hypericin Elemental analysis of cultured carcinoma cells and tumour tissue using the NUS nuclear microscope SERS Nanotechnology and Imaging

Photodynamic therapy and anti-angiogenesis Fluorescence correlation spectroscopy of hypericin in vitro Optical Coherence Tomography Analysis of biofluids for early cancer detection using miniaturized microdevices such as HPLC and Flowcytometry

Molecular analysis of tumors from renal transplant recipients Molecular analysis of colorectal tumours


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator / laboratory

Local Collaborator(s)

Research Centre

Project Title

A/PROF ANN LEE

Dr Lai Poh San

Department of Paediatrics, NUH

Dr Eric Yap

DMRI

Dr Tien Sim Leng

Division of Cytogenetics, Department of Pathology, SGH Gleneagles Medical Centre Tan Tock Seng Hospital

Microsatellite analysis of tumour suppressor genes in cancer Novel strategies for detecting gene amplification in cancer Array CGH analysis of AML

Laboratory of Molecular Oncology (cont’d)

Dr Wong Sin Yew Dr Sun Yong Jiang A/PROF CAROLINE LEE

Molecular studies on Mycobacterium tuberculosis

A/Prof London Lucien Ooi A/Prof Kon Oi Lian Dr Tan Soo Yong A/Prof Samuel S. Chong Prof Edmund Lee Dr Tan Eng King Dr Ken Sung Wing Kin A/Prof Liu Wen-Tso

Liver Cancer Research Laboratory, NCCS Lab of Applied Human Genetics, NCCS Tan Tock Seng Hospital Pediatrics Dept, NUS Pharmacology Dept, NUS Dept of Neurology, Singapore General Hospital School of Computing, NUS Department of Environmental Science and Engineering

Functional Genomics of HCC

Dr Albert Ty Dr See Siew Ju Dr Chumpon Chan Dr John Thomas Dr Yeo Tseng Tsai Dr Helmut Rumpel Dr Chou Ning Dr Elisabeth Cheah Prof Malcolm Paterson Dr Ou Keli Dr Ranjiv Sivanandan

Dept of Neurology, NNI (SGH)

Brain tumor stem cell and chemotherapy

Dept of Neurosurgery, NNI (TTSH) Dept of Diagnostic Radiology, SGH Dept of Neurosurgery, NUH Dept of Pathology, SGH Lab of Genome Maintenance, NCCS Agenica Research Pte Ltd Dept of General Surgery, SGH

Celecoxib induced glioma necrosis O6-meG genotoxicity and DNA repair (MMR) Proteomics identification of MMR complex Head & Neck cancer stem cell

Dr Wong Wai Keong Dr Chan Weng Hoong Dr Ong Hock Soo Prof Yap Wai Ming Dr Chau Yuk-Ping Dr Lai Siang Hui Prof Roger Beuerman Dr Zhou Lei A/Prof Kon Oi Lian Dr Newman Sze Dr Tony Lim

Dept of General Surgery, SGH

Gastric Cancer

DR BALRAM CHOWBAY

Prof Edmund Lee

Dept of Pharmacology, Faculty of Medicine, NUS

Laboratory of Clinical Pharmacology

Dr Tan Eng Huat

Dept of Medical Oncology, NCCS

Laboratory of Liver Cancer Functional Genomics

A/PROF WONG MENG CHEONG Brain Tumour Research Laboratory

DR MAC HO MENG FATT Laboratory of Oncoproteomics

Dr Simon Ong

Dr Toh Han Chong

Pharmacogenetics and HCC Pharmacogentics of ABC transporters Genetics of ABC transporters Functional Genomics of HCC SNP chips

Dept of Neurosurgery, NNI (SGH)

Dept of Pathology, SGH Health Sciences Authority Singapore Eye Research Institute

NTU Dept of Pathology, SGH Pharmacogenetics of drug metabolising enzymes and drug transporters in Asians Pharmacogenetics pathways and PK/PD of irinotecan in NPC patients Improved individualisation of treatment and dose selection in cancer patients by genotyping A phase I dose-finding study using a chronomodulated dose-intesified (CMDI) regimen of Xeloda and oxaliplatin (XELOX) as either a first- or second-line therapy in patients with advanced metastatic colorectal cancer from a single institution Pharmacokinetics of cyclosporin A in cancer patients undergoing mini-transplant

Local Collaborators

75


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator /laboratory

Local Collaborator(s)

Research Centre

Project Title

DR BALRAM CHOWBAY

Dr Peter Ang

Dept of Medical Oncology, NCCS

In vivo detection of multidrug resistant phenotype in breast cancer patients for neoadjuvant chemotherapy by scintimammography using 99m Tc-sestamibi scan and genotyping A pharmacogenomics study for breast cancer patients undergoing adjuvant chemotherapy with doxorubicin (A)/cyclophosphamide (C) and/or weekly paclitaxel Influence of genetic polymorphisms in drug metabolising enzymes on warfarin dose and intrinsic clearance in Asian patients Pharmacokinetics of cyclosporin A and busulphan in cancer patients undergoing mini-transplant Pharmacokinetics of Zometa in multiple myeloma patients Pharmacogenetics & PKPD profiling of irinotecan in Asian cancer patients Proteomics profiling in patients receiving anticoagulant therapy

Laboratory of Clinical Pharmacology (cont’d)

Dr Wong Zee Wan

Dr Lee Lai Heng

Dept of Haematology, SGH

Dr William Hwang Dr Gerard Teoh

DR JOSEPH WEE Head, Division of Clinical Trials & Epidemiological Sciences

Dr Goh Boon Cher

Dept of Haematology-Oncology, SGH

A/Prof William Chen Wei Ning

NTU

Dr Tan Puay Hoon Mr Wong Chow Yin

Dept of Pathology, SGH Dept of Surgery, SGH

Dr Alex Chang

Dept of Oncology, John Hopkins Int Med Centre, S’pore Dept of General Surgery, SGH Dept of Oncology, John Hopkins Int Med Centre, S’pore Dept of General Surgery, SGH

A/P Pierce Chow Dr Hsieh Wenson Dr Cheow Peng Chung A/P Pierce Chow Dr Alexander Chung Yaw Fui Dr Law Ngai Moh Dr Tan Chee Kiat Dr Tan Yu Meng Dr Goh Boon Cher A/P Koh Tong San Dr Helmut Rumpel Dr Yong Wei Peng Dr Ross Soo Dr Lee Soo Chin Dr Gan Yu Unn Dr Tan Yu Meng Dr Tan Bien Soo Dr Richard Lo

Dr Tay Eng Hseon Dr Ho Tew Hong Dr Tay Sun Kuie Dr A Ilancheran Dr Lim Siew Eng Dr Benjamin WL Tham Dr Timothy YK Lim

76

Local Collaborators

Dept of Int Med, SGH Dept of Gastroenterology, SGH Dept of General Surgery, SGH Dept of Hematology-Oncology, NUH School of Electrical and Electronic Engineering Dept of Diagnostic Radiology, SGH Dept of Hematology-Oncology, NUH

Dept of Diagnostic Radiology, SGH Dept of Surgical Oncology, NCCS Dept of Diagnostic Radiology, SGH

Gynecologic Oncology Unit, KKWCH Dept of Obstetrics & Gynaecology, SGH Dept of Obstetrics & Gynaecology, NUH Dept of Medical Oncology, NUH Gynecologic Oncology Unit, KKWCH

Randomised Phase II trial of Neoadjuvant weekly Paclitaxel plus Carboplatin compared to weekly Paclitaxel alone, followed in both arms by Doxorubicin and Cyclophosphamide for Operable or Locally Advanced Basal-like subtype Breast Cancer correlating BRCA-1RNA and Protein expression with Carboplatin response. A Phase I Study of Rapamycin in combination with Bevacizumab in patients with Unresectable Hepatocellular Carcinoma

A Phase II trial of Oxaliplatin / Adriamycin / 5 FU in continuous infusion / interferon alfa-2b (OXAFI) combination as neoadjuvant therapy in unresectable non-metastatic hepatocellular carcinoma

The use of dynamic contrast-enhanced MR imaging (DCE MRI) and dynamic contrastenhanced CT imaging (DCE CT) as a biomarker for effectiveness of anti-angiogenesis therapy.

A Phase III Randomised study to evaluate Survival of patients treated with Taloporfin Sodium (LS11) and Interstitial Light Emitting Diodes (LED) as compared to the Standard of Care Therapies in the treatment of Unresectable Hepatocellular Carcinoma (HCC) Prospective phase II study of neoadjuvant Docetaxel-Cisplatin Chemotherapy followed by concurrent Cisplatin-Radiotherapy in locally advanced cervical cancer


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Principal Investigator /laboratory

Local Collaborator(s)

Research Centre

Project Title

DR JOSEPH WEE Head, Division of Clinical Trials & Epidemiological Sciences (cont’d)

A/Prof Christopher Cheng Dr Weber Lau

Dept of Urology, SGH

A Phase II Study of Docetaxel plus Carboplatin in chemonaive Hormone-Refractory Prostate Cancer patients

DR TAN SAY BENG Senior Biostatistician

A/P Saw Seang Mei

Department of COFM, NUS

Myopia in Singapore children

DR GAO FEI Biostatistician

Dr Eric Lye

National Dental Centre

A prospective study on wound healing following extractions in post irradiated jaws

DR LI HUIHUA Biostatistician

Ha Tam Cam

National Cancer Centre Singapore

Tai Bee Choo

National University of Singapore

XRCC1 gene polymorphisms and the risk of breast cancer RNASEL gene polymorphisms and the risk of prostate cancer

MS HEE SIEW WAN Biostatistician

Tan Say Beng, Tan Sze Huey

National Cancer Centre Singapore

Melissa Teo

Hepatobiliary Service, Department of Surgery, SGH Mount Elizabeth Oncology Centre, Mount Elizabeth Hospital

Khor Tong Hong

DR HA TAM CAM Epidemiologist

Dr Li Hui Hua Dr Poon Choy Yoke

National Cancer Centre Singapore National Dental Centre

Dr Peter Ang

National Cancer Centre Singapore

Phase II oncology trials with time-to-event endpoints Metastectomy for non-colorectal, nonneuroendocrine liver secondaries Radical radiotherapy with high-dose rate (HDR) brachtherapy for uterine cervix cancer long-term results Clodronate and Breast Cancer Survival Oral Lichen Planus and Oral Squamous Cell Carcinoma Epidemiology of Breast Cancer in Singapore The incidence of axillary lymph node metastases in tumours less than or equal to one centimetre Patterns of Hormone Receptor Status in Asian Women with Breast Cancer

Local Collaborators

77


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

MANPOWER DEVELOPMENT FY2006

Clinicians trained / undergoing training for MSc or PhD: University / Institute

Academic Pursuit (MSc / PhD / MD)

Name

Supervising Principal Investigator

NUS

MD (Awarded 2007) PhD Candidate

Dr Chan Chung-Yip Dr Benita Tan Dr Alvin Eng Dr Grace Pang Dr Karen Yap Dr Brian Goh Dr Victor Lee Tsuen Wen Dr Wong Jen San

A/Prof Caroline Lee Dr Patrick Tan Prof Kon Oi Lian A/Prof Caroline Lee Prof Chia Kee Seng / A/Prof Ann Lee A/Prof Malini Olivo Dr Patrick Tan Prof Kon Oi Lian

NUS / Karolinksa Inst NUS

MSc Candidate

Research Staff trained / undergoing training for MSc or PhD: University / Institute

Academic Pursuit (MSc / PhD / MD)

Name

Supervising Principal Investigator

NUS

PhD (Awarded 2007)

Munich, Vienna NUS

PhD (Awarded 2006)

Constance Saw Lim Shen Kiat Tan Poi Kiang Gwee Paichung Tang Kun Amit Aggarwal Phoon Yee Peng Loke Yee Chong Nam Shin Yuen R Bhuvaneswari Wang Suk Mei Caine Leong Iqbal Dulloo Kaia Davis Kala Ramaseshan Kho Kiang Wei Lau Wen Min Liu Bee Hui Ong Choon Kiat Ren Jianwei Suman Lal Toh Wen Hong Wang Jingbo Wang Yu Wang Zihua William Chin Yu Kun Heidi Cheng Lai Ling Bhuvana Shridar Lai Liyun

A/Prof Malini Olivo Dr Ganesan Gopalan Prof Hui Kam Man A/Prof Caroline Lee

PhD (Thesis Submitted 2006) MSc (Awarded 2007) PhD Candidate

NUS (SMA) NUS

78

MSc Candidate

MANPOWER DEVELOPMENT FY2006

Dr Patrick Tan A/Prof Caroline Lee Dr Tan Say Beng A/Prof Kanaga Sabapathy A/Prof Malini Olivo Prof Hui Kam Man A/Prof Huynh The Hung A/Prof Kanaga Sabapathy Dr Patrick Tan Dr Patrick Tan (co-supervisor) A/Prof Malini Olivo Prof Hui Kam Man A/Prof Huynh The Hung A/Prof Caroline Lee Dr Balram Chowbay / Prof Edmund Lee A/Prof Kanaga Sabapathy A/Prof Caroline Lee

A/Prof Malini Olivo Dr Patrick Tan Dr Mac Ho (Co-supervisor)


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

Postgraduate Attachment Programme: University / Institute

Year

Post graduate student

Supervising Principal Investigator

BSc (Hons), NUS

FY2006

Toh Soo Ting Yao Man Melissa Chong Huilin Li Jun Lee Sing

A/Prof Caroline Lee

PhD, NUS PhD, NTU

A/Prof Malini Olivo

Overseas Students trained / undergoing training as exchange students, etc: University / Institute

Academic Pursuit

Name

Supervising Principal Investigator

Univ. of Melbourne

Advanced Medical Science (AMS) Program for 4th year Medical Students

A/Prof Caroline Lee

Technische Universit채t M체nchen, Germany

LAOTSE Exchange Program for a 3-month research attachment as part of MSc Degree

Amy Tai Yee Phei Tan Xueling Hildegard Isolde Dietlinde Mack Birgit Piater

University / Polytechnic Industrial attachment students: University / Junior College (JC)/ Polytechnic (Poly)

Year

student

Supervising Principal Investigator

Nanyang Poly

FY2006

Geraldine Low Toh Li Zhen Christine Tan Emily Peh Rachael Wan Su Chen Joanne, Lim Siok Liu Raudhah BTAbdull Hamid Christine Chin Jay Toh Daphne Lalwani Ling Hsien Wen Marcus Wang YuPing Wan May Yang Priscilla Ker Yi

A/Prof Ann Lee

NTU

NUS(Hons) Republic Poly Temasek Poly

NTU

FY2007

A/Prof Malini Olivo A/Prof Ann Lee A/Prof Malini Olivo Dr Balram Chowbay Dr Ganesan Gopalan A/Prof Malini Olivo Dr Balram Chowbay Dr Ganesan Gopalan

A/Prof Malini Olivo

MANPOWER DEVELOPMENT FY2006

79


National Cancer Centre Singapore Humphrey Oei Institute of Cancer Research

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.

Translational Medicine: Bench to Bedside or Bedside to Bench 8 November 2006, National Cancer Centre Singapore

Distinguished Speaker Dr Sydney Brenner Nobel Laureate in Medicine 2002 Chairman, Biomedical Research Council, A*STAR Senior Distinguished Fellow, Crick-Jacobs Centre, Salk Institute

Dr Sydney Brenner is an internationally renowned scientist. He obtained his Doctorate of Philosophy at Oxford University, England in 1954. He is the founding father of molecular genetics and has contributed to the scientific community in many areas such as genomics and developmental biology. He has also personally trained several local scientists. Throughout his outstanding scientific career, he was awarded several major prizes including the Royal Medal by the Royal Society of London, the Albert Lasar Award, the Kyoto Prize in 1990 and the Nobel Prize in Physiology or Medicine in 2002. The Nobel Prize was awarded by the Nobel Assembly at Karolinska Institutet and jointly shared with H Robert Horvitz and John E Sulston in recognition of their discoveries related to genetic regulation of organ development and programmed cell death.

The Origins of Pandemic Influenza 19 April 2007, National Cancer Centre Singapore

Distinguished Speaker SIR JOHN SKEHEL

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 virus. 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.

For excerpts of the lecture transcript, please e-mail corporate@nccs.com.sg

80

Distinguished lecture series


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