Hirshberg Foundation 2006 Spring Newsletter

Foundation Newsletter

Dear Family, Friends and Supporters,

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Spring 2006

men received awards for the best basic and clinical abstracts presented at the annual American Pancreatic Association meeting this past November.

t gives me great plea- My personal guest and speaker was a sure to be very special young man, Jeremy Katz, able to share who has been a continuous donor to with you the exciting findings present- the Hirshberg Foundation for the past ed at our Second Annual Symposium five years. He was 13 years old when on Pancreatic Cancer, held this past he first made a charitable contribution January at UCLA. After in honor of his many years of personal grandfather We have come a long frustration for minimal Barry Weinway in eight years: new traub. Using improvement in treatment options, the day his internet drug developments, was truly a promise skills and his new treatment options, expertise in for the future. We have new hypothesis for cell come a long way in eight rare coins, he years: new drug develhas organized activity and improved opments, new treatment online coin life expectancy, after options, new hypothesis auctions to for cell activity and imraise money diagnosis. Most proved life expectancy, us on a importantly for all of us, for after diagnosis. Most regular basis. importantly for all of hope is within the horizon Now 18 years us, hope is within the for the much needed early old, he is a horizon for the much brilliant and detection bio-markers. needed early detection caring young bio-markers. man, majoring in Aeronautical Engineering and miThe esteemed panel at our program, noring in Medical Engineering at M.I.T. whose summaries are included in this Jeremy spoke about his memories newsletter, came from the across the and love of his grandfather and left a globe. We were joined by new partici- stunned audience in tears with his paspants from Columbia University, Loma sion to make a difference in our world.

Linda University, City of Hope, VA Jeremy’s devotion reminded all of us at Greater Los Angeles Healthcare Sys- the symposium of the human tragedy tem and Cedars-Sinai Medical Center. of this disease. Next summer we hope In addition, we recognized Dr. John he will intern in the Hirshberg TransNeoptolemos from Liverpool Uni- lational Laboratory at UCLA under the versity, UK and Dr. Paul Grippo from supervision of Dr. Howard Reber.

Northwestern University. Both gentle-

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Pictured l-r: Agi Hirshberg, Jeremy Katz and Jeremy’s mom Marion I thank you for your support and dedication. Your donations are vital to our mission to increase interest in research and keep expanding our programs.

Healthcare costs are soaring, as are research costs, along with major cuts in government support. Private funding of research is mandatory in order to see progress for pancreatic cancer. Please continue your individual fundraising efforts, large and small, because we must make a difference for the newly diagnosed patients. We can not bring back our own loved ones but we can be a part of the cure and hope for pancreatic cancer victims.

Most Sincerely,

Agi Hirshberg President and Founder

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

Enrique Rozengurt,

Stephen C. Prince, CPA

D.V.M., Ph.D.

Jon Hirshberg, Trustee

Stephen J. Pandol, M.D.

Lisa Fletcher, Trustee

Hany Elsaleh,

Mike Berliner, Trustee

M.B., B.S., Ph.D. László G. Boros, M.D.

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.

Hirshberg Foundation’s Research Mission and Accomplishments

By Vay Liang W. Go, MD

UCLA Department of Medicine

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am pleased to highlight the Second Annual Agi Hirshberg Symposium on Pancreatic Cancer. With over 130 participants, this meeting has attracted participants beyond our region. The vision of the Hirshberg Foundation is to find a cure for pancreatic cancer! Since its founding seven years ago, the Hirshberg Foundation has not only established the infrastructure for pancreatic research at UCLA, but also contributed significantly

to the national agenda. Within UCLA’s research community, the foundation continues to support the Ronald S. Hirshberg Translational Pancreatic Cancer Laboratory, fellowship and pilot projects, and the stable isotope research program focused on metabolomic research at Harbor-UCLA medical center. The foundation also established the pancreatic cancer tissue bank as well as collaborative research between UCLA, West Los Angeles Veteran Administration Medical Center, and Cedar Sinai Medical Center. Furthermore, UCLA’s Center for Pancreatic Diseases has officially launched this year. At the national level, the foundation continues to award the best abstract (basic and clinical) on pancreatic cancer presented at the annual meeting of the American Pancreatic Association. The Hirshberg Foundation also hosted the reception in Recognition of Dr. Howard Reber’s 20 years of service as Secretary Treasurer of the American Pancreatic Association. In addition, other national programs of the Hirshberg Foundation continue to flourish, these include: seed grants and pilot/ feasibility programs, patient financial network support programs, co-sponsorship of national and international meetings, support networks for the Hirshberg Foundation, and increasing public

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awareness through community events.

The Hirshberg Foundation has become a national resource. We would like to highlight this year’s programs.

UCLA Center for Pancreatic Diseases

By Howard A. Reber, MD

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 pan-

creatic 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. A 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.

National Comprehensive Cancer Network Practice Guidelines on Pancreatic Cancer

By Stephen I. Shibata, MD

Department of Medical Oncology City of Hope National Medical Center

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denocarcinoma of the pancreas remains a virulent disease with fewer than 10% of patients surviving more than 5 years and improved treatments are clearly needed.

However it is important to use available therapies to their best advantage.

The National Comprehensive Cancer Network (NCCN) is an organization composed of representatives from institutions across the country with expertise in treating various malignancies including pancreatic cancer. The Pancreatic Cancer Committee carefully reviews available data and new developments and makes recommendations regarding treatment. These are available in the form of algorithms available through the NCCN web site. These guidelines are reviewed at least annually and are meant to be a resource to the oncology community. Current recommendations for treatment include evaluation for surgery as the primary curative treatment, with chemoradiation or chemotherapy for unresectable locally advanced disease. Adjuvantly, chemoradiation plus systemic chemotherapy is recommended with disagreement about the role of chemotherapy alone. Gemcitabine based chemotherapy is recommended for metastatic disease. In general, a clinical trial is a preferred option given the need for improved treatment. It is anticipated that these recommendations will undergo continued revision as treatment optimistically improves.

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Chemotherapy for Locally Advanced Unresected Pancreatic Cancer

By William H. Isacoff, MD

UCLA Division of Hematology-Oncology

Primary purpose. To evaluate the efficacy and safety of a 5 Fluorouracil (5 FU) based four drug chemotherapeutic regimen in the treatment of patients with locally advanced non- metastatic pancreatic cancer. Encouraged by the results from a pilot study at UCLA, we felt it appropriate to confirm these observations in a multi-institutional cooperative group setting.

Materials and Methods - From November 1997 to June 2001 patients with histologically proven ductal or undifferentiated stage II or III pancreatic cancer who were not eligible for curative resection were enrolled onto this study. All patients required the surgi-

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Photo l-r: Dr. Robert Fine, Agi Hirshberg, Dr. William Isacoff

cal placement of an indwelling central venous line. Treatment consisted of: 1).

5 Fluorouracil (5-FU) 200 mg/m2/day, given by continuous infusion using an ambulatory pump for four weeks followed by a one week rest. 2). Leucovorin (LV) 30 mg/m2 by intravenous bolus injection weekly on days 1, 8, 15 & 22 followed by a one week rest. 3).

Mitomycin C (Mito C) 10mg/m2 every six weeks for four doses (each dose not to exceed 15 mg, the total cumulative dose was not to exceed 60mg) 4). Dipyridamole (D) 75mg dose given orally three times daily during the 5-FU administration. Treatment was continued until disease progression, unacceptable toxicity or eligibility for surgical exploration based on CT scan criteria of resectability.

Results - Fifty patients were eligible for evaluation, 47 of whom had measurable disease. There were two complete responses and 10 partial responses (5 of which were unconfirmed by further CT evaluation) for an overall response rate of 26%. The one year survival probability was 54%. The median survival was 13.8 months, and the median time-totreatment failure was 7.3 months. Six of the responding patients underwent exploratory surgery with successful complete resection of their primary

tumor. The most common grade 3 or 4 toxicity was stomatitis. There were no treatment related deaths.

Conclusion: These results confirm the efficacy of modulated, continuous infusion 5 FU with Mito C in the treatment of patients who have locally advanced unresected pancreatic cancer and compares favorably with the outcomes that are observed with patients who are treated with radiation plus chemotherapy or regimens containing gemcitabine . Future trials should test the efficacy of standard radiation and chemotherapy, compared to full dose chemotherapy alone, without radiation.

Chemotherapy of Metastatic Pancreatic Carcinoma

By Robert Fine, MD

Division of Hematology-Oncology Columbia University Medical Center

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e have found that the combination of gemcitabine, docetaxel, and capecitabine (GTX), when administered in a specific sequence, will induce a p53 independent pathway of cell death through the MAP kinase pathway. The sequence overcomes drug resistance in PC cells

in vitro. We have begun a prospective, phase II trial of GTX in patients with metastatic PC as first-line therapy. 23 patients with metastatic PC, ECOG 0-2 were enrolled at either Columbia or a community practice. Each cycle was administered over a 21 days. Capecitabine was administered at 750 mg/m2 twice daily for 14 days. Gemcitabine (750 mg/m2 over 75 minutes) and docetaxel (30 mg/m2) were administered on days 4 and 11. Responses were measured by CT (RECIST) and PET after every three cycles. Intent-to-treat analysis was used. A response by PET was defined as a 50% reduction in SUV while a CR was an absence of uptake. Preliminary results show that GTX, elicits a promising response rate when used in metastatic P.C. PET detects a response and failure of chemotherapy earlier than CT scans. However, median survival has not yet been reached.

Saliva Test for Pancreatic Cancer

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

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he National Institute of Dental & Craniofacial Research has invested 57 million dollars in saliva diagnostic research in the past 3 years. Currently 7 engineering laboratories are developing nano-technologybased biosensors for detection of salivary analytes. In addition, 3 proteomic laboratories are actively deciphering all the proteins in saliva. UCLA is engaging in both technology development and salivary proteome cataloging to advance saliva diagnostics. Most exciting we have discovered a new and informative analyte in saliva, RNA, that can be profiled using high throughput microarray technology. Salivary RNA is high specificity and sensitivity towards oral cancer detection in saliva. Efforts and leadership are currently in place to explore if pancreatic cancer can be detection in saliva.

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Pancreatic Cancer Pharmacogenomics: Predicting Response in Pancreatic Cancer Treatment.

Pancreatic Cancer Tracer Metabolomics

Director of Pancreaticobiliary Endsocopy Division of Digestive Diseases UCLA School of Medicine

racer metabolomics is a new discipline in systems biology and is an extension of classical biochemistry. Instead of studying each individual reaction, tracer metabolomics utilizes stable isotope tracers and focuses on input/output analysis, which is the end result of interaction of multiple reactions within the cell. Changes in metabolic phenotypes can be shown graphically using metabolic phase plane analysis. The metabolic phase plane analysis also provides information regarding optimal conditions for cell growth, differentiation, proliferation and apoptosis.

Competition and complementarities among different cell types can be understood in terms of substrate competition leading to metabolic selection of phenotypes. Pancreatic intraepithelial neoplasm (PanIN) has been shown to occur in stages associated with genetic changes. Since genetic mutations are random sporadic events, the pathological changes from carcinoma in situ to malignant invasion can best be explained by metabolic selection of the mutated cells in the order of the different stages.

By James Farrell, MD.

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he majority of patients with pancreatic cancer rely upon chemotherapy with or without radiation therapy for the management of the disease. The overall response to the currently used agents is poor, although it is clear that certain subgroups of patient derive benefit from these treatments. Furthermore, the mechanism of chemoradioresistance in pancreatic cancer is poorly understood. The development of targeted therapies has increased the treatment options available to these patients. However, toxicity associated with these treatments, especially the newer treatments may be a limiting factor in their widespread use.

We hypothesize that there are tumor dependent factors which can reliably predict response to chemotherapy and radiation therapy. We also hypothesize that there are host dependent factors which can reliably predict response and toxicity to chemotherapy and radiation therapy. Using tissue from the RTOG 9704 prospective randomized adjuvant study in Pancreatic Cancer, we are studying the role of tumor dependent and host dependent factors in predicting response and toxicity to treatment.

By WN Paul Lee, MD

LA BioMed Research Institute at Harbor-UCLA Medical Center

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Fructose Metabolism in Pancreatic Cancer Cell Growth

By Anthony P. Heaney, MD, PhD Cedars-Sinai Medical Center

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eight, physical activity, and nutrition alter cancer risk and carcinogenesis for many cancers, and evidence is accumulating on the effect of these health factors on cancer prognosis and

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quality of life among cancer survivors.

Along with an increase in total energy consumption over the past few decades, a clear shift in the types of nutrients consumed in the American diet has been highlighted. Specifically, the consumption of fructose has increased dramatically, primarily because of increased consumption of beverages that are high in fructose and the consumption of other foods sweetened with sucrose and high-fructose corn syrup (HFCS). High carbohydrate intake has been hypothesized to be a risk factor for pancreatic cancer, possibly mediated by elevated levels of free insulin and insulin-like growth factor-l. Fructose feeding-induces insulin resistance, mainly due to a diminished ability of insulin to suppress hepatic glucose output. However the association between obesity, and pancreatic cancer is likely multifactorial, and in addition to insulin resistance, lipids and triglyceride levels have been associated with increased pancreatic cancer risk.

Additionally, cancer cells themselves may be able to distinguish, and

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Photo: Dr. Anthony P. Heaney and Lisa Manheim

preferentially utilize different carbohydrates, and altered glucose transporter levels have been described in some cancers. We are utilizing gene array, proteomic, and metabolomic approaches to characterize the potential mechanistic relationship between different carbohydrates and pancreatic cancer risk, and have demonstrated differential gene expression following growth of pancreatic cancer cells in fructose versus glucose. In future studies we will examine carbohydrate uptake, and transport expression (Glut 1-12), oxidative phosphorylation (Fructokinase, Phosphofructokinase-1), and signal transduction pathways to characterize the mechanisms(s) by which pancreatic cancer cells utilize carbohydrates.

Inflammation and Pancreatic Cancer

Manipulating the Lipoxygenase Pathways for Pancreatic Cancer Prevention/ Treatment

By Diane M. Harris, PhD

UCLA Center for Human Nutrition

By Guido Eibl, MD

UCLA Department of Surgery

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including macrophages and lymphocytes, which are found in inflamed tissues (e.g. wound healing), are also present in invasive pancreatic tumors.

In addition, many signaling molecules, which are critical regulators of inflammation, are also functional in pancreatic cancers. These findings strongly suggest that inflammatory signals are key regulators of pancreatic cancer development and progression. However, it is unclear whether chronic inflammation in the pancreas is sufficient for cancer development or whether it simply promotes the expansion of an already transformed cell. Understanding the importance of inflammation in pancreatic cancer is nevertheless a promising approach to identify novel targets for cancer prevention and therapy.

we and others have found that inhibition of VEGF can slow the progression of pancreatic cancer in vivo. However, these studies have also shown that this approach does not completely block tumor associated angiogenesis suggesting that other factors are involved.

Clinically, the use of humanized VEGF antibody has demonstrated some utility, but has not provided much survival advantage. Preliminary evidence in our laboratory suggests that CXC chemokines are important mediators of disordered growth and angiogenesis in pancreatic cancer. Several CXC chemokines are potent angiogenic factors and represent a unique family of cytokines that exert promotion of angiogenesis through a single receptor CXC receptor 2 (CXCR2). Blockade of CXCR2 is potentially a powerful strategy to slow angiogenesis and prevent tumorigenesis. We hypothesize that the progression of pancreatic cancer is promoted by the expression of specific angiogenic CXC chemokines and activation of the corresponding receptor, CXCR2; and that inhibition of CXCR2 will delay the growth and metastasis of pancreatic cancer related to inhibition of angiogenesis.

hronic inflammation of the pancreas is a known risk factor for human pancreatic cancer. However, many of the cellular and molecular pathways underlying and linking both processes remain largely unresolved. Many cell populations,

Role of Chemokines in Pancreatic Carcinogenesis

By O. Joe Hines, MD

UCLA Department of Surgery

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here is an urgent a need to develop new and better strategies for the treatment of pancreatic cancer. As with other solid tumors,

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ost cases of pancreatic cancer are diagnosed in individuals between 60-80 years of age, suggesting that the development of clinical years takes some time to develop. As nutritionists, we are particularly concerned with how dietary factors affect the length of this time period. The American Institute for Cancer Research concluded that some 35% of the pancreatic cancer risk is modifiable by dietary

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factors. Chronic inflammation is a critical component of the development of pancreatic cancer. The eicosanoid pathway produces many inflammatory mediators and is dependent on the metabolism of arachidonic acid, a polyunsaturated fatty acid (PUFA) found in the diet. The production of eicosanoids begins with the liberation of PUFAs, including arachidonic acid, from membrane phospholipids by the action of enzymes called phospholipases following an external signal. The three major pathways of arachidonic acid metabolism are the cyclooxygenases (COXs), the lipoxygenases (LOXs), and the cytochrome P450s. In pancreatic cancer, the main LOX pathways that have been implicated are the 5- and 12-LOX pathways, which produce the hormone-like leukotrienes. Like the COX inhibitors, inhibitors of both 5-LOX and 12-LOX have a number of actions not only in reducing inflammation, but also cell proliferation, angiogenesis, and apoptosis. Nutritional approaches to modulate the LOX pathways include through balancing dietary n-6:n-3 PUFA ratios, and natural LOX inhibitors, which can be found in a number of fruits, vegetables, culinary herbs, and botanical medicines. We are currently conducting studies to use preclinical models to understand the mechanisms of action of these dietary factors.

Trophic Factors in Pancreatic Cancer

By J. Enrique Rozengurt, DVM, PhD UCLA Division of Digestive Diseases

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nrique Rozengurt reviewed the genetic and epigenetic changes in human pancreatic cancer cell, which plays a key role in the growth and metastasis of pancreatic cancer.

Genetic changes (K-ras, p53, SMAD4, BRCA2) and epigenetic changes, including up-regulation of autocrine/ paracrine loops driven by growth-promoting factors. Classic autocrine loops are mediated by growth factors that act via tyrosine kinase receptors, typi-

cally TGF_ and EGF. Work from our laboratory is expanding the notion that growth factors that act via G-Protein coupled receptors (GPCRs) also play an important role in driving the unregulated multiplication of pancreatic cancer cells. Growth factors that utilize GPCR to broadcast messages into the cells include gut regulatory peptides such as neurotensin, gastrin, galanin, bombesin, CCK and others. GPCR-induced signaling cross-talks with TRKs, inducing synergistic biological effects such as DNA synthesis and cell multiplication. GPCRs also mediate angiogenic functions in the endothelial cells via CXC chemokines. A major element in the signaling pathways evoked by most growth factors is the activation of the protein kinase PKD, a novel enzyme discovered in our laboratory.

Recent findings demonstrate that: 1) PKD is expressed in pancreatic ductal adenocarcinoma cell lines and tissues 2) PKD can be activated by neurotensin in a dose and time dependent manner 3) PKD over expression enhances DNA synthesis and multiplication in pancreatic cancer cells. Thus, PKD is emerging as a potential novel target for pancreatic cancer treatment and research focus on growth factor signaling is an important strategy for the development of new therapeutic approaches for this devastating disease.

PKD Translocations in Pancreatic Cancer Cells

By Osvaldo Rey, PhD

UCLA Division of Digestive Diseases

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he protein kinase D (PKD) family consists of three serine/threonine protein kinases termed PKD, PKD2 and PKD3, implicated in the regulation of important biological processes such as DNA synthesis and chromatin remodeling. Our studies, using real-time imaging of genetically encoded fluorescent and photoactivatable-fluorescent PKD isozymes expressed in human pancreatic cancer

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Panc-1 cells, demonstrated that these kinases are highly mobile and that each isozyme displays a distinctive intracellular localization before and after their activation [reviewed in (1)]. An increasing amount of experimental evidence indicate that the targeting of signaling molecules to different cellular compartments is a fundamental process in the regulation of their functions. Consequently, the development of inhibitors to prevent the translocation of activated PKD isozymes to specific cellular compartments could be used as a novel approach to interfere with the propagation of signaling cascades mediated by this family of kinases.

(1) Rozengurt, E., Rey, O., and Waldron, R. T. (2005) J. Biol. Chem. 280(14), 13205-13208

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 310472-6310. 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.

Cell Death Mechanisms in Malignant and Non-Malignant Pancreatic Tissue

By Stephen J. Pandol, MD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System The presenters in this session were Stephen Pandol, Nathan Wall, Olga Mareninova and Mouad Edderkaoui.

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he session was devoted to presentations of cell death process in two major diseases of the pancreas. One was pancreatic cancer; the other pancreatitis. In both diseases there are problems with cell dying. In pancreatic cancer, the cancer cells have developed resistance mechanisms to prevent cell death. This is why the cancer cells continue to grow and overtake the body despite surgery, radiation and chemotherapy. On the other hand, in pancreatitis the cells die rapidly leading to manifestations of a severe acute illness characterized by inflammation of the pancreas, and if severe enough death of the patient.

Little was known about the biochemical details of how cells die in mammalian tissues until about 15 years ago.

The understanding of the death mechanisms came from research done to elucidate biochemical signaling pathways involved in development of a small worm called Caenorhabditis elegans or c. elgans for short. C. elegans is a small (about 1 mm long) soil nematode found in temperate regions. About 15 years ago scientists started to appreciate that similar signals mediating cell death were also in tissues of animals and man. Just during the past few years there has been a rapid acceleration of our understanding of cell death pro-

cesses in cancer and well as non cancer diseases. There is now a general consensus among scientists that treatments using agents targeted to cell death signaling systems will provide significant advances in a wide variety of cancerous and noncancerous diseases. In fact, there are emerging agents and early stage clinical trials for such agents.

The presenters each shared their work showing both molecular biological and pharmacologic approaches to attack cell death signals in both pancreatic cancer and pancreatitis. The results were very encouraging and each presenter showed how carrying their research projects forward will lead to significant advances in the treatments for pancreatic cancer and pancreatitis.

Survivin Regulation of Apoptosis in Pancreatic Cancer

By Nathan R. Wall, PhD Loma Linda University

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otential approaches for more effective pancreatic cancer therapy might include genetic based therapies that attempt to eradicate cancer cells by manipulating their intracellular genetic material with strategies ranging from restoring the function of mutated or missing tumor suppressor genes to inhibiting the function of activated oncogenes. One such strategy is to utilize the inhibitor of apoptosis protein (IAP) survivin, as a therapeutic target as it is overexpressed in the majority of pancreatic adenocarcinomas and correlates with cellular proliferation and apoptosis. Survivin has been shown to physically associate with the cyclin-dependent kinase p34cdc2 and is phosphorylated on Thr34 by p34cdc2-cyclin B1 both in vitro and in vivo. Loss of phosphorylation on Thr34

results in survivin’s dissociation of a survivin-caspase-9 anti-apoptotic complex and caspase-9-dependent apoptosis. A Thr34ÆAla mutant was created which abolished the Thr34 phosphorylation site and when overexpressed in the PANC-1 pancreatic adenocarcinoma cells, spontaneous caspase 9-dependent apoptosis resulted. We will continue to explore using Thr34ÆAla alone and in combination with chemo and radiotherapy for fighting pancreatic cancer.

Cell death in pancreatitis: Caspases protect from necrotizing pancreatitis.

Presented by Olga A. Mareninova, PhD

Abstract by O.A. Mareninova,1 K.F. Sung,1,2 P. Hong,1 A. Lugea,1 S.J. Pandol,1 I. Gukovsky,1 A.S. Gukovskaya.1 1VA Greater Los Angeles Healthcare System & University of California, Los Angeles, CA, and 2Chang Gung Memorial Hospital, Taipei, Taiwan.

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evere parenchymal necrosis is a major complication in pancreatitis. Severity of pancreatitis in animal models correlates directly with the extent of necrosis and inversely with that of apoptosis. To determine the mechanisms mediating cell death responses in experimental pancreatitis, we utilized the differences between two rodent models of cerulein pancreatitis. Pancreatitis induced by cerulein (CR) in rats is a mild disease with relatively high apoptosis and low necrosis, whereas in mice is a more severe disease with high necrosis and very little apoptosis. It was shown that the apoptosis/necrosis differences between rat and mouse CR pancreatitis are caused by caspase blockade in the mouse mod-

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el. Maintaining high XIAP levels is one mechanism of caspase blockade that leads to increased necrosis in mouse CR pancreatitis. In contrast, XIAP degradation allowed caspase activation and apoptosis in the rat model, protecting from necrosis. The results suggest that strategies designed to stimulate caspases (e.g., by inhibiting XIAP) will attenuate pancreatitis severity by promoting apoptosis and reducing necrosis.

In the Spotlight …

Heather Stevens

IGF-R Trans-activation

by Fibronectin Protects Pancreatic Cancer Cells From Apoptosis

By Mouad Edderkaoui, PhD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

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oth fibronectin and insulin-like growth factor receptor-I (IGFR) are known to play a critical role in both stimulation of growth as well as inhibition of pancreatic cancer cells death. The aim of this study is to investigate the interaction between both pro-survival pathways to determine the key protein involved in the protection of pancreatic cancer cells from death induced by fibronectin and IGF-R. Our results indicate that inhibition of IGF-R abolished the pro-survival effect of fibronectin. We found that fibronectin trans-activates IGF-R through up-regulating IGF-R phosphorylation through inhibition of the protein tyrosine phosphatase (PTP) SHP-2. Inhibiting IGF-R with both pharmacological and molecular approaches also abolished fibronectin-induced activation of downstream pro-survival signaling, in particular, expression of anti-apoptotic protein BclxL. The results suggest that targeting IGF-R would prevent pro-survival effects of both IGF and fibronectin.

They also suggest IGF-R and SHP-2 as potential therapeutic targets to induce cell death in pancreatic cancer.

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ne of the pleasures of being apart of our organization is the wonderful people we meet. Most often we become instant extended family members, bound by our quest for helping those touched by pancreatic cancer. One of our treasured friends is Heather Stevens.

Heather, with her radiant smile, dogmatic perseverance and gentle soul has been a part of our organization for the past four years. After her diagnosis of pancreatic cancer and post Whipple surgery, she joined our efforts to raise awareness and offered her help to newly diagnosed patients. We fell in love with Heather and her 14 year old son Connor instantly. We have shared wonderful times through foundation events such as the LA Cancer Challenge.

For the past two years Heather and Connor traveled with us to Vancouver to cheer on our Marathon Training Team. I know that her mere presence helped all of us finish the long race.

In 2005 her cancer unfortunately returned. A treatment available in Basel, Switzerland was suggested to Heather by her UCLA oncologist. Neuroendocrine (slow growing) tumors had been successfully treated with a novel “radiolabelled somostatin analogue octreotate”. It took the Foundation twentyfour hours to research the treatment and to decide that this procedure was an option for our Heather. This treatment was not covered by insurance for pancreatic cancer patients in the United States. A special “Hope for Heather” fund was created by friends, family and the Hirshberg Foundation to make the journey possible to Basel in three different 7-day installments.

Heather is still fighting for her life as the treatment left her immune system compromised with her bone marrow in a depleted state. Her endurance and positive attitude is an inspiration to all of us. Her beautiful smile and hopeful spirit is etched in our hearts. We wish her continued strength to continue to fight pancreatic cancer.

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running apparel, caps and duffle bags, which were awarded to those runners who collected pledge money. Our grand prize winners, Heidi Hockenberry and Deanne Lebowitz, each won a Roven Dino Swiss watch. Hockenberry, Team Captain of “Walk for Hock”, was there to support her husband Jon, a pancreatic cancer patient, while Lebowitz, Team Captain for Team Jerry Jacobs, raised money in memory of her father. Shelby Galton, a local preschool teacher, received a plaque for heading up the team with the most participants - over 100 members of Team Mark Galton were walking or running in memory of Shelby’s late husband Mark.

The Hirshberg Foundation Crosses the Finish Line: Winners Raise Unprecedented Amount of Money for Pancreatic Cancer Research

The 8th Annual LA Cancer Challenge, held this past October, successfully raised more than $250,000 for pancreatic cancer research – a 54% boost from last year. A record-breaking 2152 participants arrived early on a Sunday morning for the 5K, 10K and Kiddie Run and were welcomed by Agi Hirshberg of the Hirshberg Foundation. Some were dressed in festive Halloween costumes, others in athletic running attire. Many were wearing t-shirts or signs showing their support for a loved one with pancreatic cancer.

Each year, the L.A.C.C. reminds the Southern California community that the fight for a cure must go on. The event kicked off Pancreatic Awareness Month acknowledged in November.

“We are a constant reminder to Angelenos and Southern Californians alike that it is important that we continue to provide research for Pancreatic Cancer, to educate and to find a cure” said Agi Hirshberg, Founder. “It has the number 1 fatality rate of all cancers. So, it is important that we do not allow it to be the proverbial ‘forgotten stepchild’.”

She adds, “this year’s event proved that there’s hope in finding a cure based on the strong contributions and the public’s participation.”

T-shirts and goodie bags were given to all registered participants and volunteers. Under Armour and JR286 donated the prizes, including performance

“While the LA Cancer Challenge is first and foremost a fundraiser, it is also provides a unique opportunity for people living with or affected by the disease to come together, meet people in the pancreatic cancer community, and create awareness of the disease. It is an inspiring and emotional day for everyone,” explains Lisa Manheim, Event Chairman Victors of this charity run include: Adam Nevens, 25-years-old of Los Angeles, CA 5K Overall Male winner (time: 16:10); Brenda Terry, 35-yearsold of Fullerton, CA 5K Overall Female winner (time: 19:29); Fred Arapmayek, 52-years-old, 10K Overall Male winner (time: 33:15) and Mary Akor, 29-yearsold, 10K Overall Female winner (time: 38:43).

Presented by Under Armour, the LACC included a Kiddy Fair for the “little ones,” a Halloween costume contest for adults and kids, a pumpkin pancake breakfast and lots of games and prizes Other sponsors included: Paul A Hughes Family Foundation, Big 5

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

Calendar of Upcoming Events Hirshberg Marathon Training Team

Vancouver International Marathon Trip May 5-8th, 2006

For more information or to support our team, visit www.marathon. kintera.org

Sporting Goods, K-EARTH 101, JACK FM, jr286, Hows Markets, Narvid, Scott &Schwartz LLP, City National Bank, Western Bagel, Southwest Airlines, Levine Leichtman Capital Partners, Robeks, Propel Fitness Water, Roven Dino Swiss, N*SOUL Records, City National Bank, and Clif Bar.

The 9th Annual LA Cancer Challenge is scheduled for Sunday, October 29, 2006. Please contact Lisa Manheim at 310-472-6310 or visit www.

LACancerChallenge.com for further information.

Thank you!

The Hirshberg Foundation for Pancreatic Cancer Research gratefully acknowledges those individuals, families and corporations for their support. Thank you for enabling our doctors, scientists and researchers to continue their efforts towards finding a cure for this disease. Please consider becoming a supporter to the foundation. Your contributions vastly help in our research, as well as offset the printing and production of this newsletter. Our website allows you to make a fast and secure online donation Visit www.pancreatic.org to make your tax-deductible gift today.

8th Annual Hirshberg Foundation Golf Classic presented by Under Armour

Monday, May 22, 2006 Valencia Country Club

For more information contact David Hartmire at 661-799-7940

9th Annual LA Cancer Challenge presented by Under Armour

5K/10K Walk/Run

Sunday, October 29, 2006 Veterans Adminstration Grounds, West Los Angeles, CA www.LACancerChallenge.com

If you would like to sign up for our online newsletter ww w. pa n c r please e at go i cto. ohttp://www.pancreatic.org/enewsletter rg