Hirshberg Foundation 2007 Spring Newsletter

Foundation Newsletter

Spring 2007

Program has increased projects across the country. Recipients this year were selected from Johns Hopkins University, Columbia University, City of Hope, VA Greater Los Angeles Health Care System, Harbor UCLA and of course our home base at UCLA, where we can now boast about several new NIH grants.

With your extraordinary dedication and financial support, we will defeat this enemy. It will take time, but we will get it done together!

Thank you, Agi Hirshberg and Dean Gerald S. Levey

Welcome

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t is hard to believe that this year marks our 10th anniversary. My emotions are accelerated, as I am feeling a sense of accomplishment but also sorrow as the early detection we demand still remains illusive. To this day, I feel revengeful towards pancreatic cancer, which disrupts, ruins, and devastates so many wonderful families’ lives forever.

Estimated new cases continue to rise, while in four other cancers the numbers are decreasing. What that means is that our work continues, our passion continues, our drive continues until the day comes when we can offer life saving treatment for pancreatic cancer victims.

When that day comes, we as a group will celebrate like never before!

Imagine!

This issue once again features the scientific summary of the previous years’ work, which was presented at UCLA this past February at the Agi Hirshberg Symposium. The information is tough read for most of us, yet, there is a tremendous amount of satisfaction in seeing and

reading about the research advances our scientific partners have completed to advance the understanding of what we are dealing with. Dr. Korc phrased the problem so well when he said “We need to understand what cell type gives rise to this disease, how it does it and how we can stop it.” Sounds so simple, yet obviously, it is not. In addition to the traditional research paths we are exploring saliva tests, breath tests and preventative nutritional studies. Familial registries are now available in many parts of the country, as part of the solution for early diagnosis.

Ten years ago there were things I did not know, or want to know, such as how many years would be needed to improve treatment, or how much funding of research would be necessary to accelerate this entire process. As I have said so many times over the years, time does not deter us or defeat us. We will continue our efforts until we have the answers we need!

Thank you for your faith in our Foundation and the Scientific Advisory Board who steers the course of our funding and expansion. Our annual Seed Grant

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Agi Hirshberg President and Founder

Remarks from Gerald S. Levey, MD, Dean of the Medical School Congratulations to Ms. Agi Hirshberg for establishing the Hirshberg Foundation for Pancreatic Cancer Research in honor of her late husband Ronald Hirshberg. During the last 10 years, since the founding of the Foundation, UCLA has greatly benefited from the Foundation’s generosity and support in providing the research and education structure, including the establishment of the UCLA Center for Pancreatic Diseases last year.

This is only the second pancreatic diseases center in the US after Johns Hopkins University. On behalf of UCLA School of Medicine, I wish you continuing success in finding the cure for and prevention of pancreatic cancer.

BOARD OF

SCIENTIFIC

DIRECTORS

ADVISORY BOARD

Agi Hirshberg, Founder

Vay Liang W. Go,

Lisa Manheim,

M.D, Chair

Trustee, Director

Howard A. Reber, M.D.

Michael Scott, ESQ

Murry Korc, M.D.

Stephen C. Prince, CPA

Lee Rosen, M.D.

Jon Hirshberg, Trustee

Hany Elsaleh,

Lisa Fletcher, Trustee

M.B., B.S., Ph.D.

Mike Berliner, Trustee

László G. Boros, M.D.

From Left: Dr. Howard Reber, Dr. Vay Liang Go, Dr. Murry Korc, Agi Hirshberg, Dr. Naathan R. Wall

Foundation Vision and Mission statement VISION

To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands who are diagnosed with this disease MISSION To establish a premier Pancreatic Cancer Center within UCLA for ongoing basic and clinical research on pancreatic cancer early detection and cure • To be recognized as a patient support reference source for pancreatic cancer victims and their families • To integrate and unite generations, young and old, through physical fitness participation, while creating public awareness and raising money to go towards our fight against pancreatic cancer.

• To be open to assist in funding new projects and/or programs that may improve patient care, treatment and survival of pancreatic cancer.

Third Annual Agi Hirshberg Symposium on Pancreatic Cancer Hirshberg Foundation’s Research Mission and Recent Accomplishments Vay Liang W. Go, MD

UCLA Department of Medicine

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t was 1997, Hirshberg Foundation was established by Mrs. Agi Hirshberg in memory of her late husband, Ronald S. Hirshberg who died of pancreatic cancer at the early age of 54. The mission of the Foundation is to find a cure for pancreatic cancer, to pioneer early detection methods that will lead to improved treatment options, to provide patient support and referral services for pancreatic cancer victims and their families, and to assist in funding new projects for programs that will accomplish the above mission. This year the mission was expanded to include prevention of pancreatic cancer.

In 10 short years, the Foundation has raised over $6 million for pancreatic cancer research. At UCLA, the Foundation established the Ronald S. Hirshberg Translational Pancreatic Cancer Laboratory, the Ronald S. Hirshberg Chair in Translational Pancreatic Cancer Research, and the Pancreatic Cancer Tissue Bank. At Harbor UCLA, the Foundation supported the Stable Isotope Research program in tracer metabolomics. Three years ago, a collab-

orative pancreatic cancer research program was established among Los Angeles academic centers including UCLA, the West Los Angeles Veterans Administration Medical Center, Cedars-Sinai Medical Center, City of Hope Medical Center, and Loma Linda University.

The Hirshberg Foundation continues to award the best abstract presentations during the national meeting of the American Pancreatic Association. 2006 was a joint meeting of the American Pancreatic Association and International Association of Pancreatology and the awardees were: • M. Apte, Pancreatic Research Group, The University of New South Wales, Sydney, Australia “Pancreatic Stellate cells Stimulate Pancreatic Cancer Growth and Metastasis: Findings of a Novel Orthotopic Model of Pancreatic Cancer” Pancreas 33(4):472, 2006 • Sultana, Division of Surgery and Oncology, Royal Liverpool University Hospital, Liverpool, UK “Meta-Analyses of the Management of Locally Advanced and Metastatic Pancreatic Cancer” Pancreas 33(4):499, 2006

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At the national level, the Foundation has launched a very successful seed grant program to fund pilot feasibility studies that can then go on to qualify for National Institutes of Health grants. The 2006-2007 pilot feasibility awards were given to the following individuals: • Kristina Kisfalvi, MD, PhD UCLA Division of Digestive Diseases Title: Role of protein kinase D (PKD) in the proliferation of pancreatic cancer cells • Harold Frucht, MD Columbia University, New York, NY Title: Pancreatic Physiology in the Screening and Early Detection of Human Pancreatic Adenocarcinoma • Christopher Wolfgang, MD Johns Hopkins University, Baltimore, MD Title: Targeting Lipid Mediations of Pancreatic Cancer Growth • Diane M. Harris, PhD UCLA Center for Human Nutrition Title: Fatty Acid Synthase Inhibitors in Pancreatic Cancer • Joseph Kim, MD City of Hope National Medical Center and Beckman Research Institute, Duarte, CA Title: Targeting Chemokine Receptor CXCR4 to Prevent Pancreatic Cancer Over the years the pilot feasibility program has resulted in some key NIH funding and these include: • Guido Eibl, MD R01 CA 104027 The Role of COX2 and PPAR-g in Pancreatic Cancer • Anna Gukovskaya, PhD R01 CA 119025-01 NADPH Oxidase and Pancreatic Cancer Cell Survival • Nathan R. Wall, PhD P20 MD 001632-02 Project 3, Oxidative Stress-Induced Cellular Survival Pathways in Pancreatic Cancer • Aurelia Lugea, PhD R03 AA 016008 Urokinase-Type Plasminogen Activator System and Pancreatic Stellate Cells

• Oscar Joe Hines, MD R21 CA 1207803 Role of CXCr2 in Pancreatic Cancer • Other collaborative center grants and individual initiated grants are currently under consideration by NIH. The research accomplishments are highlighted by various presentations in this symposium. We in the scientific community would like to extend our heartfelt gratitude to the Hirshberg Foundation for their support and wish the Foundation continued success in carrying out its noble mission.

Recent Insights into the Pathobiology of Pancreatic Cancer Murray Korc, MD

Department of Medicine Dartmouth Hitchcock Medical Center and Dartmouth Medical School

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ancreatic ductal adenocarcinoma (PDAC) is associated with many genetic alterations, including mutations in the K-ras oncogene, the p53 and Smad4 tumor suppressor genes, and the p16 cell cycle regulating gene. In addition, there is over expression of multiple tyrosine kinase receptors and their ligands that enhance the proliferation of cancer cells, adjoining fibroblasts (stroma), and tumor blood vessel cells. These changes occur in conjunction with loss of responsiveness to the usual growth inhibitory signals generated by transforming growth factor beta (TGF-b) proteins. The stroma itself produces and stores angiogenic factors. Therefore, in addition to attacking the cancer cells, one needs to target both the blood vessels and stroma in this disease. We have sought to delineate the stromal contribution to PDAC progression by using VEGF Trap, which sequesters vascular endothelial growth factor A (VEGF-A) as well as related ligands, a soluble type II transforming growth factor (TGF) receptor to sequester TGF-bs, and an antibody that targets connective tissue growth factor (CTGF) which is up-regulated by TGF-bs. All three strategies attenuated tumor growth, metastasis and angiogenesis. We also found that a small molecule called SAHA increases the sensitivity of pancreatic cancer cells to the actions of gemcitabine. All these approaches, in addition to strategies that neutralize the tyrosine kinase receptors that promote cancer cell growth, could be used to design novel therapies. However, the best cure is prevention, and to prevent pancreatic cancer we need to understand which cell type gives rise to this disease, how it does it, and how we can stop it. Recent work in our laboratory using lineage tracing studies in genetically modified mice points to a small pool of pancreatic progenitor cells as a possible culprit.

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Can Saliva Provide an Early Detection for Pancreatic Cancer?

David T.W. Wong, DMD, DMSc UCLA School of Dentistry

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he ability to monitor health status, disease onset and progression, and treatment outcome through non-invasive means is a most desirable goal in health care promotion and delivery. There are two prerequisites to materialize this goal: specific biomarkers associated with a health or disease state and the technologies to discriminate the biomarkers. Being able to engage these prerequisites on a noninvasive biofluid like saliva will be very helpful. A recent initiative catalyzed by the National Institute of Dental & Craniofacial Research (NIDCR) has created a roadmap to achieve these goals through the use of oral fluids as the diagnostic medium to scrutinize the health and/or disease status of individuals. This is an ideal opportunity to bridge state of the art saliva-based biosensors, optimized to disease discriminatory salivary biomarkers, for diagnostic applications. Oral fluid (saliva) is a perfect medium to be explored for health and disease surveillance. The translational applications and opportunities are enormous. Pancreatic cancer is a high priority cancer to be explored for saliva-based detection. Efforts are in progress to explore the diagnostic potential of saliva for pancreatic cancer detection.

The UCLA School of Dentistry is engaged in both the technology development as well as molecular target harnessing from saliva for disease detection. The development of the Oral Fluid NanoSensor Test (OFNASET) and the cataloging of the human salivary proteome as well as the discovery of the salivary transcriptome for disease detection importantly advance this non-invasive diagnostic portfolio.

Supported by PHS grants RO1 DE15970, UO1 DE 16275 and UO1 DE017790.

Introduction and an Update on Center Activities

Howard A. Reber, MD and Barbara Clerkin, RN, MPH UCLA Department of Surgery

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he UCLA Center for Pancreatic Diseases is a multidisciplinary clinical center for the coordinated management of patients with pancreatic diseases, including acute and chronic pancreatitis, and various pancreatic neoplasms, especially pancreatic adenocarcinoma. It resides administratively within the Department of Surgery, but includes a variety of individuals who provide expertise in the areas commonly called upon to manage these patients. Specific disciplines represented include Surgical and Medical Oncology, Radiation Oncology, Digestive Diseases, Gastrointestinal Pathology, and Gastrointestinal Radiology with a total of 17 multi-disciplinary participating faculty. Barbara Clerkin, the Nurse Coordinator, oversees and manages patient flow, and is responsible for a variety of issues that include maintenance of a clinical database, patient education and inpatient and outpatient care. Physicians in the Center see and treat approximately 1000 new patients a year. The Center Director is Howard A. Reber, MD, Professor and Chief of Gastrointestinal Surgery; Associate Director is O. Joe Hines, MD, Associate Professor of Surgery.

The UCLA Center for Pancreatic Diseases holds two management conferences weekly: • Every Thursday (7:30-8:30 am), participants at the multidisciplinary conference discuss challenging pancreaticobiliary cases.

Following discussions among experienced radiologists, gastroenterologists, oncologists and surgeons, where recommendations are made on how to best manage each case.

• Every Tuesday (5:00-6:00 pm), all surgical cases from the previous

week are discussed, focusing on operative findings, pathologic assessment of the resected material, and plans for additional therapy.

Today’s experimental therapies may be tomorrow’s cutting-edge solutions.

Patients may be eligible to participate in a variety of clinical trials that aim to better understand pancreatic disease and apply new treatments. These trials include: • EUS- or CT-guided gene therapy for pancreatic cancer • Early detection of pancreatic cancer – CAPS 3 trial

Screening for Early Pancreatic Cancer at UCLA: The CAPS3 Study James J. Farrell, MD

UCLA Division of Digestive Diseases

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CLA is participating in a prospective, multicenter, translational collaborative study (The CAPS3) that will screen for early pancreatic cancer in a large number of high-risk individuals across the US using state-of-the-art imaging technology such as endoscopic ultrasound, computed tomography, magnetic resonance imaging and magnetic resonance cholangiopancreatography, and a panel of candidate biomarkers. This study was proposed by the Cancer of the Pancreas Screening (CAPS) Consortium and will be carried out at UCLA. The high-risk individuals to be screened include adults with at least two firstdegree relatives with pancreatic cancer, patients with Peutz-Jeghers Syndrome, or carriers of BRCA2. This screening study can hopefully detect early curable pancreatic cancer and potentially lower the incidence and mortality rates of pancreatic cancer down the road.

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What’s New in Surgery?

O. Joe Hines, MD

UCLA Department of Surgery

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ver the past 50 years, surgery for pancreatic cancer has evolved into safe operation offering patients a potential for cure.

Despite the continued expansion of our understanding of this disease, no significant improvement in survival has occurred. However, we are now observing an improvement in survival for patients who are resected. The five-year survival following resection has doubled to 35%. This is probably due to improved operative technique, better selection and the increased utilization of postoperative chemotherapy.

This is good news for patients who are operative candidates, but only 10-15% of patients are candidates for resection at the time of presentation since most have locally advanced or metastatic disease. For these patients palliative procedures including gastrojejunostomy and biliary drainage operations can be completed laparoscopically allowing for faster recovery, and, therefore, the ability to start chemotherapy.

It is our hope that we will ultimately be able to identify early precancerous lesions of the pancreas with regularity and remove these with the laparoscopic. For some patients this is already happening and will likely expand when early detection becomes available for this devastating disease.

Progress in Medical Oncology Edward Garon, MD

UCLA Division of Hematology/Oncology

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hemotherapy is of proven benefit in pancreatic cancer patients presenting with all stages of disease. Gemcitabine has been the most active chemotherapeutic in pancreatic cancer clinical trials. Chemotherapy with gemcitabine after sur-

gical resection decreases the risk of recurrent cancer. At UCLA, patients who have undergone resection of pancreatic cancer have the option of enrolling in a clinical study in which all patients receive gemcitabine, and some also receive inactivated, genetically engineered yeast. The yeast are designed to prime the patient’s immune system against the most commonly mutated protein in pancreatic cancer, thereby preventing recurrence.

In patients in whom pancreatic cancer has spread beyond the pancreas, patients receiving gemcitabine plus either erlotinib or capecitabine have improved survival compared to patients treated with gemcitabine alone. Unfortunately, recent studies adding other chemotherapeutic agents such as oxaliplatin and bevacizumab to gemcitabine have not demonstrated better outcomes than gemcitabine alone. Traditionally, chemotherapy plus radiation has been used to treat pancreatic cancer that has not spread beyond the pancreas but cannot be resected secondary to involvement of nearby blood vessels. Although most of these patients will not be able to undergo resection, chemotherapy with or without radiation therapy can sometimes shrink the tumor enough to allow surgical removal. At UCLA, these patients have the option of enrolling in a clinical study of chemotherapy and radiation in which two out of three patients also have a gene therapy virus (TNFerade‘) injected into their tumor.

The injected gene is designed to kill cancer cells when activated by radiation. In addition to standard therapies and clinical trials specific for pancreatic cancer patients, patients with pancreatic cancer are eligible for many early studies of novel drugs, including many targeted therapies.

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Oxidative Stress and Pancreatic Cancer: Dietary Implications Stephen J. Pandol, MD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

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esults of experiments presented in the 3rd Annual Agi Hirshberg Symposium demonstrate that important role the oxidant stress plays in promoting pancreatic cancer growth as well as making it resistant to dying with treatment. Reactive oxygen species (or ROS) are the oxidants in cancer cells. The experiments presented indicate that ROS are increased in the cancer cells due to both activation of systems that produce them and inhibition of anti-oxidant systems. The combination leads to an augmentation of the amount of ROS in the cancer cells. Further, cancer cell growth factors promote the increase even further by increasing the activity the pro-oxidant generators and inhibiting the formation of the anti-oxidant systems.

How do ROS work to promote cancer growth? This is an emerging field of cancer research and there are potentially multiple mechanisms involved.

Information presented at the Symposium shows the role of ROS in setting up resistance to cancer cell death through interference with the death signaling pathways in cancer cells. In fact, methods to neutralize ROS with anti-oxidants or to inhibit ROS generating systems results in removal of the interference with death signals that occur in cancer cells allowing them to proceed to dying. Thus, methods can be developed to take advantage of these findings to augment current therapy.

What about diet? Evidence from population studies indicates a protective effect of fruits and vegetables in the diet on cancer including pancreatic cancer. Many of these benefits can be from the anti-oxidants that are present in these foods. More spe-

cifically, a recent paper demonstrates that the dietary intake of lycopene provided mainly by tomatoes in the diet was associated with a statistically significant 31% reduction in pancreatic cancer risk in men. Lycopene is one of the most potent phytochemical antioxidants through its ability to trap singlet oxygen.

In sum, results of studies indicating how oxidants work to promote the resistance of cancer cells to dying along with more information on how dietary molecules work in this process will prevent new strategies for both treatment of pancreatic cancer and dietary prevention or pancreatic cancer.

Reactive Oxygen Species: Pro-Survival Factor in Pancreatic Cancer Anna S. Gukovskaya, PhD

UCLA Department of Medicine Pancreatic Research Group VA Greater Los Angeles Healthcare System

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rowth factors, such as insulinlike growth factor (IGF)-I protect pancreatic cancer (PaCa) cells from death. We recently showed that reactive oxygen species (ROS) produced by NADPH oxidase Nox4 mediate the anti-apoptotic effect of growth factors. Here we examine the mechanisms of the anti-apoptotic role of NADPH oxidase. We hypothesized that ROS produced by NADPH oxidase inhibit key protein tyrosine phosphatases (PTPs) and thus sustain the activation of kinases mediating anti-apoptotic pathways in PaCa cells. Transfections and pharmacologic inhibition were used to assess the effects of NADPH oxidase on JAK2 kinase, the phosphatase LMW-PTP, and apoptosis. We found that one target of ROS is JAK2, an important anti-apoptotic kinase in PaCa cells. Both IGF-I and serum induced biphasic JAK2 phosphorylation, with a rapid (minutes) and transient 1st phase, and a slow and sustained (24-72 h) 2nd

phase. Nox4 mediated the sustained phase of JAK2 phosphorylation, which is required for the anti-apoptotic effects of IGF-I and serum. Transfection experiments identified the phosphatase LMWPTP as a negative regulator of sustained JAK2 phosphorylation. Growth factors inhibited LMW-PTP through its oxidation by NADPH oxidase. LMW-PTP colocalizes with Nox4 both in PaCa cells and in human pancreatic adenocarcinoma. The results suggest a novel signaling pathway, in which NADPH oxidase activation results in inhibition of PTPs, such as LMW-PTP, leading, in turn, to enhanced and sustained phosphorylation of kinases, such as JAK2, and suppression of apoptosis. This pathway mediates the pro-survival effect of ROS and suggests new targets for treatment of pancreatic cancer.

The Role of Dietary Fat and Oxidative Stress in Activation of Survival Pathways in Pancreatic Cancer Nathan R. Wall, PhD

Department of Biochemistry & Microbiology Loma Linda University

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urvivin is a member of the Inhibitor of Apoptosis (IAP) family of proteins, and is highly expressed in all cancers but absent in normal tissue. Expression level correlates with chemo- and radioresistance, as well as poor prognosis in pancreatic cancer patients. The mechanisms for upregulation of Survivin in cells undergoing stress associated with tumor development and the tumor microenvironment are not well understood. We therefore analyzed three transcription factors that have been associated with stress activity: HIF-1, p75/LEDGF, and YY1, while hypothesizing their contribution to survivin upregulation. Examination of the 5’ flanking region of human survivin revealed the presence of multiple putative HIF-1, p75/LEDGF, and YY1transcription factor binding domains.

PANC-1 cells were transfected with

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nested deletions of the Survivin promoter, ranging from short (+230 bp) to long (+6280 bp) in order to study basal and stress-induced regulation with luciferase reporter assays. Cells overexpressing HIF-1 showed a 2-3 fold transactivation of all promoter constructs tested, which was further increased by chemically-induced hypoxia using cobalt chloride. p75/LEDGF overexpression resulted in weak transactivation.

However, as early as 3 hours after treatment with the chemotherapeutic agent docetaxel, a further increase in survivin promoter activity was recorded. Surprisingly, YY1 overexpression lead to an approximate 10-fold repression of all Survivin promoter constructs. YY1 involvement in Survivin promoter repression was confirmed using siRNA directed against YY1. These studies showed that knockdown of YY1 releases the Survivin promoter from the observed repression and leads to a 3-4 fold increase in promoter activity above basal level. Cells treated with thapsigargin, an inducer of endoplasmic reticulum stress and a known inducer of YY1, showed an 8-fold decrease in basal Survivin promoter activity, a value very similar to what is seen with YY1 overexpression alone. Collectively, these findings identify both basal and stress-induced transcriptional requirements of survivin gene expression.

While HIF-1 and p75/LEDGF may be in part responsible for the increased expression of Survivin in tumor tissue, YY1 may also be induced under stressful conditions to negatively regulate Survivin, suggesting that it is the balance of these transcription factors, and likely others, that play an important role in the development of cancer and its resistance to treatment.

Pancreatic Cancer Cell Resistance to Dying and Bcl-2 Proteins Izumi Ohno, MD

UCLA Department of Medicine Pancreatic Research Group VA Greater Los Angeles Healthcare System

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ackground and Aims: Pancreatic cancer cells are resistant to apoptosis. One mechanism of the resistance is through anti-apoptotic Bcl-2 proteins, which inhibit mitochondrial permeabilization, a key mediator of apoptosis. We hypothesize that Bcl-2 and Bcl-xL proteins inhibit apoptosis, partly through inhibiting a major prosurvival factor, NF-kB. Method: Bcl-2 and Bcl-xL were inhibited pharmacologically by commercially available BH3I-2’ and HA-14 in MIA PaCa-2 and PANC-1 cells. FCCP and rotenone were used to inhibit ROS production in PaCa cells. We measured apoptosis with Cell Death ELISA and Annexin V/PI staining using flow cytometry; cytochrome c release by Western blot; reactive oxygen species (ROS), with the fluorescent dye DCF using flow cytometry. Mitochondria were isolated from PaCa cells by differential centrifugation. In isolated mitochondria, we measured the effects of BH3I2’ and HA-14 on __m, respiration and ROS using, TPP+ and Clark electrodes and the fluorescent dye Amplex-Red, respectively. NF-kB activity was measured by EMSA. Results: Specific Bcl-2/Bcl-xL inhibitors dose- and time-dependently increased apoptosis in PaCa cells. The inhibitors induced apoptosis in the range of concentrations (25-100 _M) at which they inhibited Bcl-2/Bcl-xL activities, as measured by fluorescence polarization assay. Bcl-2/Bcl-xL inhibitors stimulated apoptotic permeabilization resulting in cytochrome c release and loss of YDm. The loss of YDm induced

by Bcl-2/Bcl-xL inhibitors resulted in a decrease of mitochondrial ROS production in PaCa cells. Bcl-2/Bcl-xL inhibitors also block NF-kB, a prosurvival

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factor in PaCa cells, likely through the inhibition of ROS. Conclusion: Bcl-2/Bcl-xL promotes survival of pancreatic cancer cells at least in part by their ability to increase ROS production. The ROS, in turn, may induce NF-kB activation, which inhibits apoptosis and promote proliferation.

Insulin Growth Factor in Pancreatic Carcinogenesis J. Enrique Rozengurt, DVM, PhD

Hirshberg Chair in Pancreatic Cancer Research UCLA Division of Digestive Diseases

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ultiple lines of experimental, epidemiological and clinical evidence support the notion that a crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling systems plays a critical role in the regulation of normal physiological functions as well as in the pathogenesis of a variety of abnormal processes. In particular, epidemiological studies have linked hyperinsulinemia and Type II diabetes with increased risk for developing a variety of clinically aggressive cancers of several tissues, including pancreatic ductal adenocarcinoma. However, the precise molecular mechanism(s) mediating the interaction between the insulin receptor and GPCR signaling systems remains poorly understood.

The results presented in this lecture show that exposure of ductal pancreatic adenocarcinoma BxPc-3, HPAF-II and PANC-1 cells to insulin for as little as 1 min rapidly enhanced the magnitude and the rate of increase in intracellular Ca2+ concentration produced by the GPCR agonists bradykinin, angiotensin II, vasopressin, neurotensin and bombesin. The potentiating effect of insulin was dose-dependent and it was produced in response to Gq proteincoupled, but not Gi protein-coupled, receptor agonists. Real-time imaging of single cells showed that treatment with insulin enhances the rate and

magnitude of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] hydrolysis and generation of Ins(1,4,5)P3 in response to GPCR stimulation.

Short-term treatment with rapamycin, a potent and selective TORC1 inhibitor, completely abrogated the ability of insulin to increase the rate and magnitude of Ca2+ signaling and production of Ins(1,4,5)P3 in response to bradykinin stimulation, indicating that insulin potentiates Gq protein-coupled receptor signaling through an mTOR-dependent pathway.

We propose that the potentiation of GPCR signaling by insulin provides a mechanism by which insulin enhances cellular responsiveness to Gq proteincoupled receptor agonists, including GPCR-mediated autocrine and paracrine growth-stimulatory loops in pancreatic cancer cells.

How the Desmoplasia (Fibrosis) of Pancreatic Cancer Promotes Growth of the Cancer Mouad Edderkaoui, PhD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

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ancreatic cancer has a characteristic of marked desmoplasia which is a remarkable increase in extracellular matrix (ECM) that infiltrates and envelopes the cancer.

ECM proteins mediate adhesion and invasiveness of cancer cells. The recent work of Vaquero et al and Edderkaoui et al showed that Fibronectin, a member of the ECM proteins, as well as the growth factor insulin-like growth factor-I (IGF-I) play critical role in the protection of pancreatic cancer cells from death, especially apoptosis. Of note, resistance to apoptosis is a main raison for the resistance of pancreatic cancer to different treatments. The present study shows that IGF-I receptor mediates the pro-survival effect of fibronetin. Fibro-

netcin trans-activates IGF-I receptor through recruitment of protein tyrosine phosphatase SHP-2. This recruitment prevents SHP-2 from dephosphorylating IGF-IR leading to a sustained phosphorylation/activation of IGF-I receptor and activation of a down-stream anti-apoptotic pathway that involves Akt and Bcl-xl proteins. The effect of fibronectin is mediated by b3 integrin receptor but not b1 integrin. This mechanism is of critical importance because it shows that IGF-I receptor is the key protein that mediates pro-survival effects of two major environmental factors. This data will allow us to propose novel therapeutic strategies that inhibit at the same time two protective pathways of pancreatic cancer cells from death leading to a higher stimulation of apoptosis and thus overcome pancreatic cancer resistance to chemo and radiation therapies.

formation to see if they slow pancreatic cancer growth and/or cause cancer cell death. We will use specific measures of cell life and death, as well as advanced techniques that allow a comprehensive view of all the cancer cell metabolic pathways, to determine if the fat synthetic pathway may be a reasonable target for designing drug and/or nutritional approaches to combat pancreatic cancer. Results from these studies are expected to provide rationale for clinical studies to confirm fatty acid synthesis as a marker of early pancreatic cancer in humans and potentially a target for drug and/or nutritional intervention.

Inhibition of Fatty Acid Synthase as a Potential Molecular Target in Pancreatic Cancer

Joseph Kim, MD

Diane M. Harris, PhD

UCLA Center for Human Nutrition

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n spite of the fact that pancreatic cancer is one of the most deadly of all cancers, there is little information on potential agents, including nutritional factors, that may prevent pancreatic cancer, and a great need for identification of biochemical signs of early disease. Studies in other cancer types tell us that cancer cells need to make fat for survival, and inhibition of the fatty acid synthetic pathway by drugs and/or nutritional factors may prevent or reduce cancer formation.

We have been funded for a project to see if this concept applies also to pancreatic cancer. We plan to use both drug and natural agents that inhibit fat

Targeting Chemokine Receptor CXCR4 to Prevent Pancreatic Cancer Department of General Oncologic Surgery City of Hope National Medical Center

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espite our best therapeutic agents, pancreatic cancer remains a highly aggressive disease with an overall dismal prognosis.

The estimated 33,730 new cases of pancreatic cancer in 2006 are nearly equal to the projected 32,300 deaths. A primary reason for this poor outcome is that the invasive and metastatic features of pancreatic cancer are relatively resistant to all of our current treatment modalities.

Even when surgery remains an option, early recurrence is common and uniformly fatal. Accordingly, pancreatic cancer is among the leading causes of cancer-related deaths in the United States, with 5-year survival rates, even for early-stage disease, an abysmally low 10-20%.

Recent studies have identified the importance of particular cell surface receptors in pancreatic cancer. Specifically, the activation of chemokine receptor

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CXCR4 has been shown to result in enhanced invasive and metastatic features in pancreatic cancer, perhaps partly accounting for early and frequent metastasis. Our research group has discovered that CXCR4 signaling may have a critical role in the early stages that lead from a normal pancreas to pancreatic intraepithelial neoplasia (PanIN), the apparent precursor lesion to invasive pancreatic cancer.

In our initial studies, we learned that activation of CXCR4 resulted in the growth and proliferation of PanIN cells. When we blocked CXCR4 with a specific drug inhibitor, we prevented PanIN proliferation. Our future studies are aimed to determine whether we can prevent the transition of normal pancreas to PanIN in a mouse model.

If our findings confirm the importance of CXCR4 in the development of pancreatic cancer, then our studies will provide the initial evidence and rationale to target CXCR4 in patients with pancreatic cancer.

Smad4 deficiency Yields Earlier Development of Pancreatic Cancer in Conditional Pten Knockout Mouse

Michael J. Mendoza, MD1,2 & Hong Wu, MD, PhD2

1UCLA Department of Molecular and Medical Pharmacology 2UCLA Division of Digestive Diseases

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-Ras is the most common mutation identified to date, mutated in a majority of PanIN (pancreatic intraepithelial neoplasia) lesions and in 90% of PDA. K-Ras signals downstream through two major pathways: PI3K-Akt and Raf-MEK pathways. K-Ras knock-in mouse models have recently reproduced the human disease progression of PanIN to overt PDA. PTEN is one of the most frequently mutated genes in human cancer and is the central negative reg-

ulator of the PI3K-Akt pathway. Pten is mutated or has altered expression in approximately 45% of PDA. To further our understanding of the pathogenesis of PDA we sought to generate a mouse model that conditionally mutated Pten and Smad4. Smad4 is a downstream signaling protein for the TGF-_ pathway, is mutated in 55% of human PDA, and loss of expression yields a poor prognosis. We used a conditional Pten knockout mouse that we initially crossbred with a Pdx1-Cre mouse (which allowed us to restrict the gene knockout only to the pancreas) to establish a Pdx1-Cre; Ptenlox/lox colony which we subsequently crossbred with a Smad4 knockout mouse.

Cancer presence in the Pdx1-Cre Ptenlox/lox; Smad4lox/lox is 100%. There is early development of PanIN lesions beginning as early as 4 weeks. The median survival for Pdx1-Cre PtenL/ L; Smad4L/L vs. PtenL/L; Smad4L/+ vs. PtenL/L;Smad+/+ are 202 vs. 264 vs. 358 days. We have identified local invasion into duodenum, stomach; micrometastases to liver, and macrometastases to lung. Invasion into local organs results in biliary and small intestinal obstruction. Pten mutation alone in our conditional mouse model recapitulates human PDA with subsequent death at approximately 12 months. Concomitant mutation of the TGF-_ pathway decreases the median survival by 40% with local and distant invasion. We are currently evaluating novel synergistic molecular mechanisms between the PI3K and TGF-_ pathways.

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How You Can Help

Donate Your Car, RV, or Boat!

Are you thinking of selling or trading in an old car, boat or RV? Why not donate it to the Hirshberg Foundation instead? Simply contact Lisa Manheim at 310-4726310. We will make all the arrangements to conveniently and quickly pick-up your car donation at no cost to you. We handle the title transfer requirements and provide you with a tax deductible donation receipt at the time of pick-up. As a charitable contribution your car donation could make a big difference.

We Can’t Say It Enough …Thank you!

At the Foundation office, there are days that can feel down right depressing. Whether we are answering calls from a family member of a newly diagnosed patient, to processing donations received after yet another funeral, to trying to plan a fundraiser on a shoestring budget, some days are more challenging than others.

Hope or You can Help,” chose to help.

We hope their actions will motivate others to help as well. In addition to the five persons we featured there are about five hundred we did not. There are people who, over the past ten years, have given us gifts of their money or their time on a continual basis, and we would like to thank them for their repeated efforts.

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And then, the email will come through, the letter will arrive in the mail or the call will be received. And, in an instant, we are motivated. We are reminded why we work here and what we are fighting for. The message I am referring to is when one person lets us know that they have done “something” to help, whether it is by planning their own event, sending a donation in lieu of exchanging holiday gifts, hosting a garage sale/car wash/golf tournament, serving on a committee or doing one of a million other things to help.

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Within this newsletter we featured five stories about some incredible people who, to paraphrase our motto “You can

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Anton Schiff - for his continuous support Ed and Sara Mandel, Agi’s parents - for their wisdom and guidance Teri Hughes-Velona – for her energy and passion and the endless support of the Paul A Hughes Family Foundation Brooke Jenkins – for remembering us when he closes a deal Stanley Black – for his personal support and for the support of the Linda Tallen and David Paul Kane Education and Research Foundation Amy Nelson and Nelson Art, for regularly donating a portion of the proceeds from the sale of her greeting cards

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Ilene & Allison Kaplan – for organizing the Purseonality fundraising events twice yearly Anonymous- for the mystery of your generosity during your illness and for your continued gift after you lost your battle.

Virginia Mertz-Wall - for your generosity every year The late Marilyn A. Locke – for remembering us in your will Alice Shoub – for your continued annual support in memory of Donald A. Shoub To all past and present members of the LA Cancer Challenge Planning Committee and the Hirshberg Golf Classic Committee – thank you for helping us plan incredible events that raise both money and awareness for pancreatic cancer.

Thank you to each and every supporter of the Foundation. We will all celebrate together when we win this battle!

Yo u CA n H o p e o r Yo u C a n H e l p T M

Owner of Pappo Pays Tribute to his Papa

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hef John Thiel dreamed of opening a restaurant. His father’s passion for food and wine inspired Thiel to become a chef, and together they spoke of running a business. In the Fall of 2005, John realized his dream by opening Pappo, a Mediterranean Restaurant located in his hometown of Alameda, California.

The only missing ingredient which would have made the opening perfect was his father, William J. Thiel, who died of pancreatic cancer in 2000 at the age of 59.

The one-year celebration is a significant milestone in the restaurant industry, so as Pappo’s first anniversary approached, John knew the celebration had to be unique. “We have been very fortunate since the day we opened and I wanted to use this anniversary as an opportunity to give back.” He added, “I was motivated to pay tribute and respect to my father who was unable to be a part of this dream of mine.”

John did just that. Last October, he organized a dinner party for 44 people that raised almost $6,000 for the Foundation. Held at Pappo (which means “to eat” in Latin), they charged a set price for a five-course dinner paired with world class wines from Robert Chadderdon. A silent auction was held, featuring donated pieces of art and

private collections of wine. The staff at Pappo’s volunteered their time and more than 90% of the food and wine was donated from the restaurants purveyors. This allowed Thiel to keep the cost of the event down and thus maximize the proceeds he could donate to the Foundation.

“I wanted the proceeds to go directly to The Hirshberg Foundation to further the research of pancreatic cancer because that is what my father had.

I thought maybe one day it could help my sister, my brothers, myself or any

other family member, as I understand this cancer to be hereditary.”

After the event, Thiel described the overall experience as “great” and found comfort in the fact that so many of his friends and family would come out to support what he felt was a very worthwhile cause. “I am very happy to be in a position where I could host something like this, and I look forward to making it an annual event.”

When asked what his father would have thought of the event had he had been alive to attend, John said “I think my father would have been very proud of me and he would have loved the meal.”

How You Can Help Wear purple! Show your support by wearing a Purple Wristband or a Foundation T-Shirt, Sweatshirt or Hat. The Wristband is embossed with our motto “You can hope, or you can help” as well as our web address.

Bands are $2.00 each and are sold in packs of 10. All apparel items are embroidered with our logo, and are available for purchase on our website.

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Art Event Honors a Grandmother’s Passion

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mily Foster and her grandmother Betty Geraci, who she affectionately called “Meme”, shared a passion for art. When Emily was a young girl, her mother and grandmother took her to local museums and galleries where they marveled at various splendid works from numerous talented artists.

In 2004, Emily’s family received the shattering news that Geraci had been diagnosed with Pancreatic Cancer. Like many patients, the doctors predicted Geraci had between three and six months to live. In 2006, after long outliving the doctors’ prediction, Meme was slowly beginning to lose her battle with the disease. Although her grandmother was still alive and fighting, Emily was feeling helpless. “My grand-

mother was getting sicker and I just wanted to do something.” So rather than just hope, she decided to try and help!

Emily turned to art, a passion she shared with her Meme, and began organizing several local artists for a benefit.

Just as Emily began implementing her idea for an art show, her grandmother succumbed to the disease. Emily devoted the next six months to planning event, which she named, “Art Can Cure”. She created a website, solicited sponsors and secured local artists to participate and donate their art. On the evening of December 2nd, 2006 Art Can Cure was held in Savannah’s Orleans Hall. Through the sale of tickets and art, the event raised more than $5,000 for the Hirshberg Foundation.

When asked why she chose the Foundation as the event’s beneficiary, Emily replied, “I found the Hirshberg Foundation after Googling “pancreatic cancer”. I read Agi’s story and cried as I read it. The spirit in which The Hirshberg Foundation was created moved me and I knew then where I wanted to help. “

“I think she would have had a ball!” Emily said excitedly when asked what her grandmother would have thought of the event. “She never got to see Art Can Cure come together but I believe she was there in spirit. As the local artwork hung and music played and the people chatted, I could almost envision my Meme going from painting to painting, asking questions and being the life of the party,” Emily continued.

Despite her personal loss and all the effort Emily put into the planning the event, she would like to host one again.

“I worked really hard for six months and when the building was set up and guests were there, I was happier than I had ever been. I honestly felt like doing a happy dance and saying ‘I did it!’!” She added, “I would like to follow in Agi’s footsteps and build a relationship with local hospitals and cancer programs while always having a bond with The Hirshberg Foundation.”

I honestly felt like doing a happy dance and saying ‘I did it!’!”

Ways You Can Help Find A Cure for Pancreatic Cancer •

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Honor your loved ones on birthdays, anniversaries, Mothers Day/Fathers Day, Christmas, Hanukkah, Easter, Valentines Day or any other occasion with a donation to the Hirshberg Foundation.

Ask your friends or relatives to give a donation on your birthday or other special occasion in lieu of a gift.

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When you host a party, dinner or house warming, let guests know that you would prefer that a small donation be given to the Hirshberg Foundation in lieu of a hostess gift.

Host a fund raising dinner.

Invite your guests to a party or dinner at your home and request a twenty-five to fifty dollar donation per person. The

donation is tax deductible, and so is the expense of the party.

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Ask your doctor if you can leave Hirshberg Pancreatic Cancer Research Center brochures in the office waiting room, as a resource for other patients. Call other oncologists in your area, and ask them to do the same.

Chicago Fundraiser runs 26.2 to honor the dad she never met Editors Note: Last year we were contacted by Hillary Cavan, a young woman from Chicago, who was training to run in the LaSalle Bank Chicago Marathon, and wanted to raise money for the Hirshberg Foundation in conjunction with her training. After the marathon, we asked her to answer some questions about her experience.

What motivated you to train for the Chicago Marathon?

I ran the Marathon for my Father who passed away from Pancreatic Cancer. Although, I never had the opportunity to meet my father I have always felt as though he is with me every step I take. He was diagnosed with this cancer when mother was eight months pregnant with me. I was born on the day of his funeral, three days after he had passed away.

Why did you choose to raise funds for the Hirshberg Foundation?

When I committed myself to this marathon there was not a charity that was closer to my heart. Having the opportunity to raise money throughout my training & running the marathon with extra support and pride is something I will never forget. It had been 24 years but I never want my family to forget what an amazing man he was and how important it is to keep cancer research in the minds of everyone.

What were your results?

I raised just over $5,000 with the help of my loving friends, family & co-workers and I completed the marathon in 4 hours, 15 minutes!

How was the overall experience for you?

It was an incredible experience that I will never forget. My father was an amazing man and being able to raise this money in his honor was something I will hold so close to my heart. I think it helped remind everyone of how unforgettable he is and brought back amazing memories for all.

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Ask your church, synagogue, school, or country club to hold a fund raiser in your beloved’s honor – a dance, dinner, golf or tennis tournament, bake sale, car wash, rummage sale.

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If you live in Southern California, participate in our two annual fundraising events, the Hirshberg Golf Classic in the Spring, and the LA Cancer

What do you think your dad would have thought about you running a marathon?

I know my Dad was with me every step of the way. My long training runs, my solo runs during the week and most importantly all 26.2 miles! It was a very cold & grey day in Chicago and at mile 23 the sun just peaked out a bit; I know that his spirit was shining down on me.

Will you ever run 26.2 miles again?

I would love to run another Marathon in the near future & will definitely look forward to raising money for the Hirshberg Foundation!

Challenge 5K/10K Run in the Fall. Become a member of the planning committee, volunteer on event day, or raise pledges for participating.

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Hold a fundraiser in your local area. A walk-a-thon, bicycle race, ski event or dance marathon are just a few ideas. Don’t be afraid to start small. We can offer suggestions and guidance.

Help build our mailing list.

Send us names of friends, relatives and colleagues who have been touched by pancreatic or other gastrointestinal cancer.

We will keep them informed of upcoming events and current findings.

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Order flowers and gift baskets through our online store.

L. A. Cancer Challenge 5K/10K to Celebrate 10 Years

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he Hirshberg Foundation is celebrating the Tenth Anniversary of the L.A. Cancer Challenge (LACC) 5K/10K Walk/Run and Kids Can Cure Fun Run on Sunday, October 28, 2007. More than 2,750 men, women and children of all ages are expected to attend, many dressed in festive Halloween costumes.

After last year’s record-breaking results (more than $350,000 was raised) the goal for this anniversary year is to raise $500, 000.

Presented by Under Armour Performance Apparel, the LACC will feature a Kids Can Cure 1K Race, a Halloween Kid Zone, a Food & Drink Expo, a Halloween Costume Parade and our tradi-

tional Pumpkin Pancake Breakfast. Past corporate sponsors have included Big 5 Sporting Goods, Naked Juice, Southwest Airlines, Western Bagel.

For more information or to register, start a team or become a sponsor, please visit www.LACancerChallenge.com. There is a $25 registration fee, which includes an Under Armour LACC performance shirt and runner’s gift bag. For $10, children 13 years old and younger can register for the Kids Can Cure Fun Run by visiting www.KidsCanCure.org.

Remembering My Grandfather

off every piece, $1700 had been raised. A few months later, I tried my luck at another auction, and with even more success than my first auction, decided to keep running them whenever possible.

My grandfather was an aviation enthusiast, and in the summer of 1998, I inherited his passion. Standing outside his hold house in London, I saw the heavy jets on approach to Heathrow, and, combined with many recent flights, I realized that I, too, loved aviation. I finally had an interest that allowed me to get close to my grandfather, but I was only given a year and a half before he was taken from me, with so much knowledge and so many stories left unshared.

It started in 10th grade when I did a biology research project on pancreatic cancer. Three years after my grandfather succumbed to his pancreatic cancer following a valiant battle, I finally understood what had taken him, and I wanted to do what I could to keep others from experiencing the pain and loss I felt. But, in 10th grade, there wasn’t much that I could do. At least, not at first glance.

An avid coin collector, I turned to an online message board where I regularly post, and asked if anyone would be willing to donate coins for me to auction, with all proceeds benefiting the Hirshberg Foundation. To my amazement, donations poured in, and by the time I had finished auctioning

My grandfather left this world failing to complete two things.

First, he never had the opportunity to go to college, so he was never able to become an aeronautical engineer. Secondly, he was unable to defeat pancreatic cancer. Soon after arriving at MIT, I realized that I had the power to finish those two tasks for him. During MIT’s month-long January break my freshman year, I held another auction, which raised $4000. Then, this past summer, I spent my summer in Los Angeles with Agi, working at the Hirshberg labs at UCLA and watching planes at LAX in my spare time. I left Los Angeles more passionate than ever about helping the foundation.

When I returned to class this past fall as a sophomore, I began the rigorous aeronautical engineering curriculum, on track to complete one of my grandfather’s unfinished tasks.

To help complete the other, I held another January auction for the Foundation.

Since 10th grade, six auctions have raised over $28,000, $20,000 of which has gone to the Hirshberg Foundation. While it’s true that Agi has told me I’m crazy (in the best possible way) for doing what I’ve done, I’d like to think that I’ve just done my part to remember a great man. So long as you remember, no one is truly gone.

By Jeremy Katz

If you would like to sign up for our online newsletter please go to http://www.pancreatic.org/enewsletter

Scottyfest Golf Tournament is a Hole In One

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his past Fall, Ferguson Enterprises hosted the 2nd Annual Scottyfest, a golf tournament honoring the memory of their former employee Scott Shively, who lost his life to Pancreatic Cancer in 2005. Held at the Sunol Valley Golf and Country Club in Northern California, more than 100 golfers participated in the event which raised $10,000 for the Hirshberg Foundation for Pancreatic Cancer Research.

Nick Colletti, Ferguson’s General Manager and one of Scott’s good friends has been actively involved in planning Scottyfest along with many other Ferguson associates. Originally, however, Scottyfest was not intended to be an “event”, according to Colletti.

“When Scott was diagnosed and realized that he did not have much time,” recalls Colletti, “we talked about some things that he might want to do with friends and family. Scott wanted nothing more than to get a bunch of his buddies and co-workers together for a day of golf.”

So, they gathered up some friends and family, booked some tee times and were ready to enjoy a round with Scott. Unfortunately Scott lost his battle with the disease a mere four days before our outing.” With the blessing of Scott’s family, including his wife Bernice and daughters Cambria and Erin, they proceeded with their plans. That “day of golf” became the first Scottyfest. “We just had our 2nd Annual tourney last fall and we plan on making Scottyfest an annual event,” stated Nick.

Donations from many of Ferguson’s representatives and manufacturers helped cover the costs of the tournament. Following the shotgun start, players were confronted with many on-course contests including Closest to the Pin and Longest Drive. At the end of their round, players were treated to a 19th Hole Reception that included dinner, a

raffle, and an awards presentation in the clubhouse. Colletti summed the day up by saying “I was very proud of the turn out, as well as the great day that everyone had!”

Ferguson, along with Scott’s family and many of his friends, are motivated to keep the memory and spirit of Scott alive by raising money and awareness each year at Scottyfest and supporting the mission of the Hirshberg Foundation with their support and generosity. “Scott was a giant of a man, not only in size, but in heart. He was one of the strongest individuals that I have known,” said Colletti.

The Scottyfest committee, made up of Ferguson associates and members of Scott’s family, has already started working on this year’s tournament, with a goal of making the event better than ever, while celebrating the life of their friend and co-worker. When asked what Scott would have thought about the event, Colletti remarked, “Scott would have thought this event was pretty great, but he would have laughed and asked what all the fuss was about!”

“We just had our 2nd Annual tourney last fall and we plan on making Scottyfest an annual event,”

How You Can Help Order flowers and gift baskets from www.pancreatic.flow-

erpetal.com and 12% of your purchases will support the Hirshberg Foundation for Pancreatic Cancer Research. Send flowers and gifts for Mothers Day, birthdays, graduations, anniversaries and holidays -- with every purchase you make, you will be helping to find a cure for pancreatic cancer.

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