Hirshberg Foundation 2009 Spring Newsletter

HIRSHBERG FOUNDATION FOR PANCREATIC CANCER RESEARCH Foundation Newsletter 2009

Welcome Agi Hirshberg Founder & CEO Hirshberg Foundation for Pancreatic Cancer Research

For many years I have used the opening page of this newsletter as a means to thank you for your continuous, unwavering support and to provide a realistic picture of where we are in research, as well as where we need to go to realize our common dream of finding the cure for pancreatic cancer.

Agi Hirshberg, Dr. Grippo, Dr. Go

the ability for early diagnosis, dollars spent and survival and dollars spent and the decrease in deaths, renewed my rage once again. How is it possible that pancreatic cancer remains the number one cause of cancer deaths?

Sleepless nights, frustration and anger brought me to the same conclusion unless we continue to fund research more aggressively than ever before, the distance between life and death will remain elusive and unsolved.

Within these pages you’ll read about the 5th Agi Hirshberg Symposium at UCLA, held for the medical and research communities, as well as for patients and supporters. Our Patients & Supporters session, appropriately called Pancreas 101, presented a realistic view of the challenges that the medical community faces in its quest for meaningful treatment options. For me, the most shocking part of the day came in the form of a few presentation slides. As I faced the statistics on an oversized screen, larger than life numbers jumped at me and shocked me to my core once again. To see the direct correlation between dollars spent and

Years ago, I spoke at an American Pancreatic Association meeting, where I told the scientific audience that our Foundation would be the financial partner to the research community and we would remain partners until we could offer pain-free, long lives to pancreatic cancer patients. At no time are these words more important than now. In these challenging economic times, private funding is the engine that drives research. Increasing the number of new studies we fund, increases our chances of discovering a key to a cure.

Imagine if we had enough money to fund all the seed grant applications that we receive each year! We currently

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Intro, Con’t fund three to five projects out of thirty-five that are submitted. Thus far, every researcher whose project we funded has published their findings in leading medical journals and all have received NIH funds for further investigations. As a result of our funding, we have recruited brilliant and talented scientists who devote their careers to our cause. Not just a year, but a lifetime. One such researcher is Dr. Paul Grippo, from Northwestern University, one of our invited speakers at the Symposium.

Our days at the Foundation are filled with a roller coaster of emotions. When we find the right doctor for a patient, we feel happy. When a scientist publishes in a major medical journal, we are glad. When we have our events and thousands of people of all ages gather and we create awareness and funds for pancreatic cancer research, we are delighted. When we hear of a person who has lived with pancreatic cancer for many years, we are elated. But all of our efforts are tempered when we hear of just one friend lost to this dreadful disease.

During the past year, many famous people - from academics to entertainers, from athletes to entrepreneurs - have been in the news because of a pancreatic cancer diagnosis. We wish those who have been touched by pancreatic cancer this year the strength, courage and determination to fight their battle. I encourage everyone to read the uplifting words of Michelle Hackbarth, who is in her eighth year of living cancer-free.

There probably isn’t a family among us who is not taking a closer look at budgets right now. Our responsibility to you and our researchers is to insure our continued ability to provide funding for our outstanding programs. Thank you for taking the time to read this newsletter, and thank you for your continuous support.

A big hug to all of you,

Agi Hirshberg Founder & CEO

Patient Spotlight: Michelle Hackbarth

From the editor: We have known Michelle Hackbarth for many years, as an exuberant, beautiful lady with a contagious smile - who happens to have pancreatic cancer. Always there to encourage newly diagnosed persons, she is a testament for positive thinking and a batch of good fortune. She is the beautiful wife of Dennis, mom to sons Michael and Keith, and math teacher to thousands of kids in Los Angeles, where she has been teaching since 1979.

In her own words, Michelle speaks about what life has been like since being diagnosed: I consider March 20, 2001, a month before my 51st birthday, as the day that my cancer was diagnosed. It was the day that my doctor, Julie Ma, told me a CAT scan revealed something in my pancreas. I knew right away that it was pancreatic cancer as my cousin, Gary, had been diagnosed with pancreatic cancer eight years earlier. He had lost his battle and died six months later at the age of 48. Since Gary had fought his disease so bravely and still lost his battle, I decided to live the last six months of my life to the fullest and forgo having any treatments. Fortunately for me, my husband Dennis had other ideas, and quickly started researching and networking. He encouraged me to interview three surgeons and five oncologists.

My symptoms were extreme exhaustion, back pain and indigestion. A 7cm tumor in the head of the pancreas was diagnosed. Surgery was attempted at UCLA, but was not completed because of vein involvement. I received approximately six months of Gemzar, Xeloda and

Celebrex. Then I underwent six weeks of radiation and 5 Fluorouracil (5-FU).

Thankfully, the tumor shrank from the size of an orange to a size of a grape in a matter of six weeks. A year after the original attempted surgery, my surgeon at UCLA, Dr. Howard Reber, was able to complete a successful “Whipple.”

Three months after the Whipple, I started a maintenance program of 2000 mg of Xeloda a day. I continued this program for 2 years.

I did not use any form of complementary or alternative medicine, but I did attempt to remove all stress from my life. I stopped drinking coffee and now drink green tea. After five years of part time teaching, I returned to work full time.

The last eight years had lots of ups and downs that can best be compared to a roller coaster ride. When I was diagnosed I quickly calculated that I would die on September 30th – just a few days after Keith would be beginning his first year of college. After the shock of my diagnosis, I felt acceptance and decided that I would make the most of my situation. Since my diagnosis I have attended Keith’s high school and college graduations and Michael’s college graduation and wedding. My first grandchild was born eight months ago.

Every time I hear about another person being diagnosed with pancreatic cancer, I feel as though I am on the roller coaster ride yet again. I have been a part of the Hirshberg Foundation family for many years and am grateful for the work that they do.

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Fifth Annual Agi Hirshberg Symposium on Pancreatic Cancer

DIRECTORS & Trustees Agi Hirshberg, President & Founder Lisa Manheim, Director Jon Hirshberg, Trustee

Introduction Vay Liang W. Go, MD

UCLA Department of Medicine

The Fifth Annual Agi Hirshberg Symposium on Pancreatic Cancer was held at the UCLA Faculty Center on Feb. 2, 2009.

There were over 200 participants in attendance. The scientific theme of the symposium focused on the pancreatitis to pancreatic cancer continuum and the role of inflammatory process in the development of pancreatic cancer, followed by a workshop on animal models for pancreatic cancer and pancreatitis. This year, the Patient and Supporter Session joined the Scientific Session where topics including Pancreas 101, human pancreas location and function, genes and epigenetics and screening of pancreatic cancer were discussed. Furthermore, updates on surgical research and FDA approved chemotherapies and current clinical trials were presented.

Ms. Agi Hirshberg opened the meeting and discussed the current limited funding of pancreatic cancer research by the federal government and the challenge and opportunities for pancreatic cancer research, cure and prevention. As in previous years, Dr. Gerald S. Levey, Vice Chancellor of Medical Sciences and Dean of School of Medicine, gave the welcoming remarks to kick off the symposium and historical perspective of the Hirshberg Foundation and expressed gratitude to Agi Hirshberg for her vision, dedication and accomplishments of the Foundation.

This year’s symposium was enriched by the 17 research projects conducted by investigators at the UCLA Center for Excellence in Pancreatic Diseases, VA Greater Los Angeles Healthcare System, Hirshberg Laboratories for Pancreatic Cancer Research, Harbor-UCLA Medical Center, and Southern California Research Center for Alcohol, Liver, and Pancreatic Diseases. The presentations were in a poster format with topics ranging from pancreatic cancer stem cells to investigation of phytochemicals from food sources in inhibiting pancreatic cancer cell proliferation and angiogenesis. In addition, the role of inflammatory processes and the relationship of pancreatitis to pancreatic cancer were also investigated.

Pancreatitis to Pancreatic Cancer Continuum Stephen Pandol, MD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

Over several decades, it has become clear that patients with chronic inflammation of the pancreas (i.e. pancreatitis) have a markedly increased incidence of pancreatic cancer. This is true for acquired pancreatitis from alcohol and tobacco abuse as well as for genetic disorders with chronic pancreatitis such as cystic fibrosis and hereditary pancreatitis. The mechanisms underlying the increased risk for pancreatic cancer in these patients have not been delineated. However, recent experiments in animals with genetically engineered mutations known to increase cancer susceptibility show that the cancer is much more likely to develop when the animals with these mutations are also subjected to pancreatitis.

To v i e w t h e c o m p l e t e S y m p o s i u m V i d e o a n d P o w e r P o i n t P r e s e n tat i o n s , v i s i t o u r w e b s i t e .

Lisa Fletcher, Communications Director Michael Berliner, Trustee Stephen C. Prince, CPA Michael Scott, LLP

SCIENTIFIC ADVISORY BOARD Vay Liang W. Go, M.D, Chair Howard A. Reber, M.D. Laszlo G. Boros, MD Murray Korc, M.D. Laurence J. Miller, M.D. Howard A. Reber, M.D Lee S. Rosen, MD

Foundation Mission statement To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year.

• To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options.

• To be recognized as a patient support reference source for pancreatic cancer patients and their families.

• To fund new projects and programs designed to improve patient care, treatment and, ultimately, pancreatic cancer survival rates.

• To integrate and unite generations, young and old, through physical fitness participation, while creating public awareness and raising money to find a cure for pancreatic cancer.

lead to strategies that we can use to prevent this cancer.

Inflammatory Processes in Pancreatic Cancer Guido Eibl, MD

UCLA Department of Surgery

The majority of patients with pancreatic cancer do not have pancreatitis, at least not clinically detectable pancreatitis. However, risk factors for pancreatic cancer are ones that are known to be associated with inflammation or cellular signals associated with inflammation in several tissues.

Thus, a plausible hypothesis for the development of pancreatic cancer is that environmental risk factors increase one or more intracellular inflammatory signaling systems; and that the inflammatory signaling system(s) promote the development of the cancer. Increasing our understanding of how environmental factors translate into increased risk for pancreatic cancer will certainly

Epidemiologic and case-control studies clearly demonstrate an association between chronic inflammation and cancer. Patients with chronic pancreatitis have about a 4% risk of developing pancreatic cancer after 20 years. This association is even more prominent in patients with childhood onset of chronic pancreatitis. Children with hereditary pancreatitis have about a 40% risk of developing pancreatic cancer at the age of 70. More recently, these data have been substantiated by genetically engineered mouse models of pancreatic carcinogenesis. Adult mice that expressed mutant Kras in the pancreas only developed pancreatic

cancer precursor lesions and pancreatic cancer in the presence of pancreatic inflammation. These new data clearly suggest a possible cause-effect relationship between chronic pancreatitis and pancreatic cancer. The increased risk of developing pancreatic cancer in patients with chronic pancreatitis is now believed to be caused by a “landscape� defect. Chronic pancreatitis leads to increased cell turn-over and repair, which statistically increases the probability of DNA damage and malignant transformation. The growth of initiated cancer cells is promoted by the inflammatory micro-environment present in chronic pancreatitis eventually leading to a clinically manifest pancreatic cancer. The microenvironment in chronic inflammatory sites, including chronic pancreatitis, consists of inflammatory cells, e.g. macrophages and lymphocytes, fibroblasts that produce and secrete extra-cellular matrix proteins, and endothelial cells that form new blood vessels. These cell populations together with the

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processes of inflammation, fibrosis, and angiogenesis are also present in pancreatic cancer. In both inflammation and cancer, cells communicate through soluble cytokines and chemokines. On the molecular levels, many signaling molecules and pathways are operative in inflammatory conditions and cancers, including reactive oxygen species, growth factors, and eicosanoids. Overall, there is great similarity between inflammation and cancer on the cellular and molecular level. This has led to the intriguing argument that targeting inflammatory processes may inhibit cancer development and growth. Epidemiologic data again support this hypothesis. Patients with regular and long-term intake of aspirin, an anti-inflammatory drug, had a significantly lower risk of certain fatal cancers. This has been confirmed experimentally in numerous studies.

Targeting inflammatory pathways usually prevent cancer development and/or inhibit cancer growth.

Data from our own laboratory have demonstrated that oral intake of a non-steroidal anti-inflammatory drug delayed the progression of pancreatic cancer precursor lesions and significantly decreased the growth of pancreatic cancers in experimental mouse models. These anti-tumor effects were caused by inhibition of the cyclooxygenase-2 enzyme which led to a reduced production of pro-inflammatory prostanoids. In addition, oral intake of fish oil significantly decreased pancreatic cancer growth in mice, which is thought to be caused by shifting the balance from pro-inflammatory to anti-inflammatory eicosanoids due to the presence of high levels of omega-3 polyunsaturated fatty acids in fish oil. Taken together, it is now clear that chronic pancreatitis increases the risk of developing and may even cause pancreatic cancer. Strategies targeting inflammatory processes may prove beneficial in preventing the development and/ or growth of pancreatic cancer. More mechanistic studies are needed to

understand the exact molecular and metabolic events underlying the transition from chronic pancreatitis to pancreatic cancer. The recently developed genetically engineered mouse models of pancreatic carcinogenesis promise to be very valuable in addressing these questions.

Autophagy in Pancreatitis Anna Gukovskaya, PhD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

Pancreatitis is a potentially lethal inflammatory disease of the pancreas, pathogenesis of which remains obscure. Pancreatitis also predisposes to the development of pancreatic cancer. We provide

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evidence that acute pancreatitis causes a profound autophagy impairment, which is responsible for two key manifestations of this disease: the accumulation of large vacuoles in acinar cells and the intra-acinar trypsinogen activation. During autophagy cytoplasmic organelles destined for degradation are sequestered in vacuoles which then fuse with lysosomes, where cargo is degraded by cathepsins family of proteases. Our results suggest that one mechanism mediating the autophagic flux retardation in pancreatitis is the impaired processing and activity of cathepsins resulting in pathologic accumulation of vacuoles in acinar cells and trypsinogen activation in acinar cells.

Analysis indicates that a number of characteristics of pancreatitis are similar to those observed in lysosomal disorders (which are mostly caused by mutations that inactivate lysosomal hydrolases or affect their delivery to lysosomes) – such as block of autophagy, impaired maturation of cathepsins, decreased protein degradation, cell vacuolization and death, and the inflammatory response . Thus, our findings indicate that pancreatitis has features of a lysosomal disease, which should be taken into consideration in designing strategies to treat or mitigate pancreatitis.

Pancreas 101 Human PancreasAnatomy and Function Stephen Pandol, MD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

The human pancreas has two major subdivisions that have distinct but interacting functions. One division is referred to as exocrine pancreas; the other as the endocrine pancreas.

The exocrine pancreas constitutes about 90% of the mass of the pancreas and is composed of two types of cellular constituents. These are the acinar cells and the duct cells. The acinar cells synthesize and store digestive enzymes.

The digestive enzymes are secreted in a water solution from the acinar cells into a ductal system that propels the secretions into the intestine. In the intestine the digestive enzymes break down meal constituents into small molecules that can be transported across the intestinal surface into the body where they are used for fuel and building blocks.

Without digestive enzyme secretion which occurs in disorders of the pancreas, the meal is not digested and the nutrients pass through the intestine without being assimilated.

The process of secretion of the digestive enzymes into the intestine is tightly regulated by ingestion of a meal. That is, the secretions only occur at a low rate between meals and markedly increase with ingestion of a meal.

This regulation is complex and includes nervous and hormonal systems and starts as soon as a meal is anticipated and ends when the constituents in the meal are “digested� to molecular nutrients that can be absorbed across the intestinal surface into the blood.

The endocrine pancreas constitutes 10% of the mass of the pancreas and is contained in structures called Islets of Langerhans. The cells of the Islets of Langerhans synthesize and store two major hormones that control our metabolism. When nutrients (i.e. glucose) are absorbed across the intestinal surface and enter the blood, they stimulate the cells of the endocrine pancreas to release insulin into the blood stream.

Insulin has several effects to move the absorbed nutrients into storage sites so that they are available for use when we are not eating. Storage sites include the liver, muscle and adipose tissue. Between meals when glucose levels fall in the blood, the insulin level also decreases but another hormone in the Islets of Langerhans, glucagon, is secreted into the blood. Glucagon circulates to the storage sites and cause release of stored glucose and fat so that they can be utilized as body fuel.

This short description of the functions of the exocrine and endocrine pancreas shows how both work in tandem to assimilate, store and utilize nutrients we ingest.

Screening for Early Pancreatic Cancer James J. Farrell, MD

UCLA Department of Digestive Diseases

The role of early detection in cancer has shown to improve survival for certain cancers, including colon and breast cancer. The possibility for early detection of pancreatic cancer may be realized by an improved understanding of the histology and molecular genetics of precursor and cancerous lesions in pancreatic carcinogenesis and the development of sensitive and specific screening test (both invasive and non-invasive) to detect early pancreatic cancer with high predictive values. The National Institute of Health and National Cancer Institute Initiative on Early Detection Research Network (EDRN) in Pancreatic Cancer have been focusing on the development and validation of new biomarkers for the detection of early pancreatic cancer. Our own program has been in search of biomarkers in the saliva using high-throughput technology and cancer screening program for high risk patients for pancreatic cancer with familial genetic risk factors and or chronic inflammatory diseases.

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Cutting Edge in Surgical Research for Pancreatic Cancer Joe Hines, MD

National Failure Statistics in Surgery

UCLA Department of Surgery

For the past five years the speakers and participants of Agi Hirshberg Symposium have met to discuss the newest information regarding pancreatic cancer. It has been common for the speakers to begin their talks describing the latest national statistics. And every winter we are reminded that an additional 500 to 1,000 more people join the 35,000 plus who are diagnosed or will die from pancreatic cancer each year.

In fact among all cancer deaths in the US, pancreatic cancer now accounts for 6% - up from 5.5% in 2005. Despite this, there is some good news, surprising news, and new news about pancreatic cancer.

The positive news is that patients who go to the operating room and have their cancer removed can expect improved survival as compared to a decade ago. Analysis of the patients from UCLA reveals that the 5 year survival rate for patients today is at least 35% with a average survival of 3 to 4 years. There are even some patients who are out 10 and 12 years from surgery. This compares to numbers a decade ago that averaged 16%. For some patients who have low grade

tumors and no evidence of spread to the lymph nodes, that number approaches 50%. Why is this? Probably because we are selecting patients better with improved radiologic imaging, the operative techniques have advanced, and more patients are receiving additional treatment like chemotherapy after the operation.

Now for the surprising news. A recent report from Chicago looking at a large national cancer data base found that at least 50% of patients with stage 1 resectable pancreatic cancer were never offered an operation in the US. This wasn’t because the patients were too sick or old - it was just that this treatment option was not offered. There is no doubt that pancreatic cancer patients face an extremely pessimistic medical community when it comes to this diagnosis. This should not be surprising since the statistics regarding

this disease are so dismal and 20-30 years ago the operation so risky. But things have definitely changed, and we need to get the word out that if you have resectable pancreatic cancer your chances of surviving the operation and for many years to come are much better.

The new news is that we have identified a protein that seems to be important in patients with pancreatic cancer. CXCL5 is elevated in the blood and tumors of many pancreatic patients, but if this protein is low your survival is 25 months longer than others. This work has come out of the laboratory and tissue bank supported by the Hirshberg Foundation and the NIH. Experiments are underway to determine if CXCL5 might be a therapeutic target for patients with pancreatic cancer.

How You Can Help

Visit our e-store, check out all of our merchandise, and show your support by making a purchase. Our newly packaged wristbands come 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. Our jewelry line includes a new purple Italian patent leather bracelet with 18 karat gold plated screw décor for $95.00. Our clothing items include a purple ribbon ladies long sleeve thermal t-shirt for $25.00.

Check out our entire e-store on our website and HELP today.

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FDA Approved Chemotherapy and Current Clinical Trials Edward Garon, MD

UCLA Division of Digestive Diseases

Chemotherapy is of proven benefit in pancreatic cancer patients presenting with all stages of disease. Gemcitabine has been the most active chemotherapeutic agent in pancreatic cancer clinical trials. New information confirms that chemotherapy with gemcitabine after surgical resection decreases the risk

of recurrent cancer. The addition of radiation in the care of patients after surgery remains controversial. 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 mutant RAS, the most commonly mutated protein in pancreatic cancer, thereby preventing recurrence. In addition a pre-surgical study of soy proteins and a post-operative study of gemcitabine plus a targeted agent will begin in the coming months.

The approach to locally advanced pancreatic cancer (disease that has not spread beyond the pancreas but cannot be resected because of involvement of nearby blood vessels) has been controversial. At some centers, chemotherapy alone is used, while at others, a combination of chemotherapy and radiation is used. 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. In addition, this therapy has the potential to be life extending. At UCLA, these patients also 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 patients with pancreatic cancer that has spread to other organs, gemcitabine chemotherapy has been the standard treatment for approximately a decade. In the last few years, there has been data indicating the possibility of improved outcomes when either erlotinib or capecitabine is added to gemcitabine. At UCLA, patients have the option of enrolling in clinical studies in this setting. In one study, patients are randomly assigned to receive gemcitabine alone, gemcitabine plus a medicine that inhibits the insulin-like growth factor receptor, or gemcitabine plus a medicine that leads to apoptosis, a process in which cells cause their own death. At a time when the cancer stops responding to gemcitabine based chemotherapy, there is evidence that patients do better when they receive a chemotherapy regimen containing a drug called oxaliplatin. Patients with pancreatic cancer are also eligible for many early studies of novel drugs, including many targeted therapies.

Progress in medical science requires well-conducted clinical trials.

This approach has led to great progress in many other diseases, including many other cancers. This approach has the potential to lead to similar advances in pancreatic cancer. If researchers can work together to generate sound scientific hypotheses that they then test in clinical trials, progress in this disease can be within our grasps.

Animal Model Workshop Transgenic Mouse Model for Pancreatic Cancer Paul Grippo, PhD

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

The recent expansion of animal models of pancreatic cancer stems from the critical need to understand disease etiology in vivo, specifically regarding genetic

alterations that contribute to cellular and tissue pathology. The benefit of establishing models that best recapitulate aspects of human disease includes employment of these models to garnish additional information concerning causal signaling pathways and to

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evaluate novel chemopreventative and therapeutic measures. There are three primary groups of rodent models that serve these purposes including: xenograft implanted, carcinogen-induced, and genetically engineered models.

Xenograft models utilize cultured or primary pancreatic cancer cells which are placed under the skin or implanted within the pancreas (or main pancreatic duct) of immunocompromised mice (nudes, SCIDs, etc).

Tumors develop quickly, and kinetics depends primarily on the amount and type of cells delivered. Subcutaneous xenografts hold the distinction of being readily observed under the skin but in a non-pancreas environment.

Orthotopic xenografts circumvent this drawback, although tumors are not grossly visible. However, use of transfected markers (GFP, etc.) do allow for realtime visualization of tumors and metastases. A clear advantage of these systems is the use of human pancreatic cancer cells, although artificial delivery does not reflect the current theory of

cancer development.

Carcinogen-induced models rely on administration of certain chemicals to generate cellular changes that rapidly lead to pancreatic cancer. The most widely-used and studied model is Syrian gold hamsters IP-injected with N-nitrosobis(2-oxopropyl)amine (BOP). More recent approaches employ azaserine in rats and 7,12-dimethylbenzanthracene (DMBA) in mice.

These models do serve well in mocking the entire range of carcinogenesis from epigenetic insult to development of cancer, usually in a timely manner.

However, the histotype (acinar carcinoma in azaserine administered rats) and adverse effects on other tissue (hepatocellular carcinoma in BOP-induced hamsters) diminish their preclinical value.

Genetically modified mice are more advanced in their design in that relevant genetic mutations can be inserted into mouse genomic DNA in both a conditional and inducible manner. The engineering and technical aspects of

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transgenesis and embryo manipulation are not trivial, though the generation of a mouse that develops spontaneous pancreatic cancer from a targeted genetic lesion is a valuable research tool. Currently, there is a broad spectrum of genes and cell targets that have been utilized to produce a variety of neoplastic lesions and cancer that can reflect many aspects of human PDAC. (The pathological assessment of tissue and cellular phenotypes derived from these models has been considered in the concurrent abstract from Dr. Dave Dawson.) To date, seven potentially distinct cell types have been targeted based on their positive expression of certain genes including elastase (EL), CK19, Pdx1, p48/ptf1a, Mist1, nestin, and K5. Of course, there may be considerable overlap in expression profiles of these genes, as evident in similar lesions that develop when using a common oncogene. Thus far, the most frequently used oncogene is mutant KRAS (which comes as no surprise given its high penetrance in human PDAC), though other gene products

have been employed (TAg, myc, TGF_, sonic hedgehog, wnt, and Cox-2).

Delivery of these genes is through: transgenics (like EL-Kras, CK19-Kras, and K5-Cox2), knockin technology (like Pdx1-, p48-, and nestin-driven cre for induction of mutant gene expression through recombination), and retroviral delivery to somatic cells (like EL-TVA/ RCAS-myc). Several of these models have been crossed into TSG knockout backgrounds (p16, p53, DPC/smad4, and Tgfbr2) as a means of generating a more aggressive phenotype – namely highly invasive, even metastatic cancer. A few of these models employ mutant p53 knockins under regulation of a LSL element (LSL-p53R172H), and one model combined loss of p16 and smad4 with oncogenic Kras. These models generate a broad array of cellular lesions, precancer, and cancer that mimic early precursor lesions, PanINs, MCNs, and IPMNs which progress to invasive disease. Inducible systems (tetracycline on/off and ERT/tamoxifen) are now being employed to restrict genetic aberrations to adult cellular compartments in the pancreas. A few of these mice have been used in combination with caerulein to induce more potent affects in pancreatic parenchyma.

models of pancreatic cancer, a systematic approach has been devised to first describe histopathologic changes and then apply them to a working formulation of diagnostic categories (Hruban ,et al, Cancer Research (2006) 66:95-106). In my presentation, I have reviewed the utility of this approach in interpreting the phenotypes of several pre-existing and more recent GEM models. Several models (typically introducing mutant KRAS alone or in combination with other genetic lesions) demonstrate precursor pancreatic intraepithelial neoplasia (mPanIN) with later progression to pancreatic adenocarcinoma with varying penetrance and kinetics, closely paralleling the histologic picture seen with human pancreatic adenocarcinoma. A variety of other mouse models using similar or identical genetic mutations but with acinar-specific promoters driving recombination demonstrate a predominance of acinar-centric morphologies with acinar-ductal metaplasia and the development of lesions with predominant acinar differentiation. However, in more recent models including those in which recombination events are targeted to mature acinar cells via an

inducible promoter, acinar or centroacinar cells appear to serve as facultative progenitors through which acinarductal metaplasia gives rise to mPanIN lesions and in certain contexts pancreatic adenocarcinoma. These models, as well as other lineage tracing studies, challenge the idea that ductal cells represent the cell of origin for PanIN and pancreatic adenocarcinoma, but require further validation as they relate to the cellular and molecular pathogenesis of human pancreatic adenocarcinoma. In addition to models of acinar neoplasia and pancreatic adenocarcinoma, GEM models engineered with other genetic lesions and a variety of recombination strategies have produced histologic mimics of nearly the full range of human exocrine pancreas neoplasia, including intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasm (MCN), solid-pseudopapillary tumors and serous cystadenoma.

While there are many parallels and similarities between human pancreatic cancer and various GEM models, it is also important to note that histologic differences can and do exist. For instance, the density and distribution

In all, these rodent models have expanded the research platform for studying various signaling pathways in vivo in order to better understand disease pathogenesis and evaluate the efficacy of novel compounds.

Histopathology of Pancreatic Cancer David Dawson, MD, PhD

UCLA Department of Pathology & Laboratory Medicine

In order to critically assess the importance of an ever-increasing number of genetically-engineered mouse (GEM)

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of a premalignant mPanIN and acinarductal metaplastic lesions appear to be greater in GEM. Likewise, while GEMs can produce pancreatic cancer that is histologically indistinguishable from that seen in humans, a broader review of GEMs and their tumor histologies as presented in the literature suggests a tendency for more prominent mixed differentiation, increased anaplastic or sarcomatoid morphology and less significant desmoplasia that that seen typically in human pancreatic cancer. In considering the cellular and molecular pathogenesis of human pancreatic adenocarcinoma, several important features of each GEM model warrants consideration, including: (1) the overall kinetics of premalignant and malignant lesions; (2) the timing and specificity of recombination events introducing genetic lesions, as well as the order in which multiple lesions arise; (3) strength and cellular specificity of the promoter used to drive transgene expression; (4) the background mouse strain that is used; (5) the inherent biological differences that exist between mice and humans and (6) the permissive or requisite role of non-genetic factors in driving tumor initiation and progression, such as inflammation, environmental exposures, diet or epigenetic alterations. To conclude, the past decade has seen the creation of several unique and promising genetically-engineered mouse models that appear to phenotypically parallel human pancreatic cancer.

Future work promises to see the use of single or combinations of these models addressing important questions related to the molecular and cellular pathogenesis of pancreatic cancer, the contribution of environmental or epigenetic factors in cancer initiation and progression, the impact of chemopreventative agents in arresting or reversing disease progression and the potential efficacy of novel gene or targeted molecular therapies.

Animal Model for Pancreatitis Stephen Pandol, MD

UCLA Department of Medicine VA Greater Los Angeles Healthcare System

Over the past several decades multiple experimental animal models of pancreatitis have been developed. These models have been used to determine the nature of the mechanisms that are important in the pathogenesis of the disease; and to test potential therapies for the disease. Some of the more commonly used models include parenteral administration of high doses of cholecystokinin analogues to mice or rats; obstruction of the pancreatic duct in rats and opossums; infusion of bile acids into the pancreatic duct of rats; administration of ethanol containing diets to rats and mice; and administration of a choline-deficient ethionine supplemented diet to mice. All of the pathobiologic processes that occur in the human pancreatitis occur in these models. The major pathobiologic

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processes are inflammation, edema, cell death from necrosis, cell death from apoptosis and fibrosis. The models vary in the relative expression of each of these pathobiologic processes. For example, some models have significant amounts of inflammation with little necrosis whereas other models have greater amounts of necrosis. Some have little fibrosis whereas others develop fibrosis.

The differences in the experimental models of pancreatitis can be utilized when using the models to determine the mechanisms underlying risk factors for pancreatic cancer. For example, to test the role of inflammation and inflammatory risk factors in mediating the increased risk, one should use models with prominent inflammation without significant necrosis or fibrosis. On the other hand, to test the role of fibrosis one should use models that progress to fibrosis. Thus, a judicious use of animal models of pancreatitis can be used to investigate mechanisms underling risk for pancreatic cancer.

A Special Thank You to Barry Lazar

by Agi Hirshberg

Several months ago, a tall angel walked into our office by the name of Barry Lazar. Tragically, he had recently lost his wife Rochelle to pancreatic cancer. He found us on the internet and was ready to go into battle mode against a disease that robbed him of his love and a life built over fifty-two years. I took Barry through the Hirshberg Laboratories at UCLA, where he met several researchers who described their current projects, made possible by the support of the Hirshberg Foundation. He was impressed with the amount of work that was being done to advance this disease, but immediately said that the severity of this cancer calls for much more awareness and increased funding. Barry started by presenting us a most generous check to be used exclusively for research. He then mailed more than one hundred letters to his friends and associates promising to match any contributions they made from $200 - $1,000. To date, thanks to Barry’s efforts, over $115,000 has been raised for the Rochelle Lazar Memorial Research Fund.

I am so grateful for Barry’s energy and passion. After twelve years of fighting this battle, I almost gave up trying to get media attention and aiming to solicit the help of celebrities who may want to lend their name to our cause. Barry, entrepreneurial by nature and passionate in spirit, will not let me get complacent and challenges me regularly to insure that we amplify the urgent need of pancreatic cancer research. I feel blessed that he came in our lives.

having some lab work done, we were called back to the office with the most profound and devastating words we’d ever heard. Dan had pancreatic cancer. They scheduled him immediately to be seen by a surgeon whom they referred to as their “whipple guy”. We went home and I got on the computer to find out exactly what that meant. We immediately learned what a terrible cancer he had been diagnosed with. Every web site gave the same information. Without this surgery, Dan would die within a few months, at the most. Surgery was our only option.

An Open Letter from Donna Schulman Donna Schulman sent us this letter, written in memory of her husband, Daniel R. Schulman, who died on September 28, 2008. Donna has recently joined our legion of supporters in the fight to find a cure.

If you are reading this newsletter, I believe that you have either been affected directly by pancreatic cancer, or know someone who has. I am one whose family member was diagnosed with pancreatic cancer on April 17, 2007. We remember the best and the worst days of our lives - that was definitely the worst day of ours.

My beautiful husband of 35 years had a simple pain in his stomach. We made a doctor’s appointment, and after

After the surgery the nightmare was just beginning!

Following a regimen of chemo, the oncologist at that hospital, which specialized in breast cancer, told us she had nothing else. We then saw pancreatic cancer specialists at three major cancer hospitals, all of whom gave us the same two options: a clinical trial or hospice, each and every time.

No help was given to us to find a clinical trial or a treatment. They did however, have no problem telling him that his death was imminent.

If you have the misfortune of being diagnosed with cancer, pray for a “good cancer.” When you are diagnosed with pancreatic cancer you are told immediately that there is nothing out there for you. There is still no diagnostic test and no hope of long term survival for pancreatic cancer patients.

We need the help of the medical and research community. With funding research comes hope and research can bring a cure! Families like mine will be allowed HOPE!!

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

Memorial & Tribute Funds The Hirshberg Foundation recently launched a new online program called Memorial & Tribute Funds, where individuals can honor or memorialize someone who has been affected by pancreatic cancer and help find a cure at the same time. Each Memorial & Tribute Fund has a standing page on our website where the creator of the fund can upload pictures, share their story, and allow friends and family to donate securely to their fund. Our funds also provide the opportunity to honor or remember someone during times of celebration, such as a wedding or birthday, or while participating in a sporting event, such as a marathon or triathlon. Funds can be created for any reason, event or occasion. To learn more about each of our Memorial & Tribute Funds, visit our website.

A special thanks to those who created our first 58 Tribute Funds (as of February 28, 2009):

Alquides Rodriguez Memorial Fund

Margaret Mora Fund

Andrew J. McKelvey (1934-2008) Memorial Fund

Marianne Johnson’s Angels Memorial Fund

Arthur A. Hammer, Jr. Memorial Fund

In Support of Team Marila – 5K Run

Arthur Guarino Memorial Fund

Marsha Tarmina Memorial Fund

Beverly Craig Memorial Fund – 1/2 Marathon

Mimma Salinas Fund

Billie Sue Bardwell Fund

Nana’s Fund

In Support of The Bradley Fund - Triathlon

In Support of Nancy Hannan’s Birthday

Bruce Swanson Memorial Fund

Nancy Herbert Fund

Climb the Hills for Matilda Fund

Ona Hilton Moody Fund

Dave Sullivan (1937-2002) Memorial Fund

Patricia A. Murphy Griffin Fund

In Support of Distance for Dave Fund - 1/2 Marathon

Patricia S. Stalcup Memorial Fund

Donald A. Kiscadden, Sr. Memorial Fund

Paul F. Lecocq Memorial Fund

Douglas Hague Fund

Penelope Royall Fund

Duane Trams Fund

Richard Sherman Fund

Ellen B. O’Hara Memorial Fund

Rita Hirshberg Fund

Emory Herring Memorial Fund

Robert J. Paroli Memorial Fund

Esther Cronin Fund

Robert Weyers Fund

Esther Grander (1929-2008) Memorial Fund

Saima (1968-2008) Memorial Fund

Flo Petko Fund

Sally Suther Memorial Fund

Frances E. Harner Fund

Sharon I. Smith Memorial Fund

Gary R. Cummings Fund

Steve Meek Memorial Fund

C. Carl Roe Memorial Fund

In Support of Steve Wesby

James M. Askew Memorial Fund

Terry Hannibal Fund

Jeffery M. Nelson Memorial Fund

The Dulce Strasser Memorial Fund

Johnny Lee Hall Memorial Fund

Van Vliet Memorial Fund

Kenneth G. Leonard Fund

Victor Contini, Sr. Memorial Fund

Kimberly Heady Fund Leonard and Myris Whitbread Fund

Wanda Davis Fund

Love for Martha Fund

Wesley Williams Fund

Marcia Polk Meyer Fund

w w w. pa n c r e at i c . o r g

Tribute Funds Spotlights Deborah Roe and the C. Carl Roe Memorial Fund C. Carl Roe passed away September 5, 2008 from complications caused by pancreatic cancer. Our goal with this fund is to raise awareness of the severity of pancreatic cancer by describing our personal experience. Our focus is to spread information about this silent but deadly disease. We want to honor this person who was so important in our lives by trying to give hope to others who will have to travel his same path. We hope to raise awareness about this disease and help raise the funds necessary to develop a better means of detection and eventually a cure. Carl was taken away too soon by a disease that does not have a symptom until well after the disease has developed. We thank everyone for your support in this fight. We will continue to support this wonderful cause until a cure has been found.

To view Carl’s story, visit: http://www.pancreatic.org/memorial/carlroe

David Bradley’s Triathlon Fund In early 2008, my mother, Eleanor, was diagnosed with this awful disease. This past summer I competed in a Half Ironman in her honor to raise awareness and money for the fight against pancreatic cancer.

Fortunately, my mother’s cancer was caught early and was operable with the Whipple Procedure.

With my fund, I wanted my friends and family to take part in my journey to compete in the Ironman 70.3 Rhode Island. The hundreds of hours I trained and the race itself, which was a 1.2 mile swim, a 56 mile bike, and 13.1 mile run, was NOTHING compared to the journey my mother, Eleanor, and others are undergoing. Last October, I completed a full Ironman in Florida and came in 9th in my age group. To date, my fund has raised more than $15,000 for the Hirshberg Foundation, in honor of my mom.

To view David’s story, visit: http://www.pancreatic.org/ memorial/bradley

Wedding & Celebrations Program This Hirshberg Foundation recently launched our new Wedding & Celebrations Program as a way for those who are blessed to be celebrating a wedding, B’nai mitzvah or other milestone to also help us find a cure. We are pleased to offer this free program so that couples can discover ways to incorporate charitable giving in their wedding celebration and beyond! More and more, people are replacing once-traditional party favors with a meaningful message on a place card or tag that lets their guests know that a donation to the Hirshberg Foundation for Pancreatic Cancer Research has been made in their honor. This program can provide a personal and memorable way to celebrate your event while supporting our research and patient services.

In each newsletter, we will highlight a couple or individual who has chosen to make a difference during a blessed time in their life.

For more information, please visit the How You Can Help section on our website, www.pancreatic.org.

Highlight: The Wedding of Lindsey Wilder & John McRobbie

Since I was a little girl, my mother, Elizabeth Wilder, and I had shared dreams of my wedding day. From the invitations and flower arrangements, to the wedding dress and cake, she and I had preplanned all of the wedding details.

By the time I got engaged at the age of 25, my mother had already been battling pancreatic cancer for over a year. I was faced with the devastating reality that my mother would not live to see me get married. Sadly, my mother lost her battle with pancreatic cancer on February 15, 2008, and like everyone else who had known and loved her, I was heart-broken.

Over the next nine months, my fiancé and I considered various options that would allow us to incorporate my mom’s spirit into our wedding. After reading about a few organizations, we stumbled upon the Hirshberg Foundation’s website and learned that their main focus is on raising funds for laboratory research in hopes of developing a cure for the cancer. Shortly after sending our contribution, we received purple ribbons for our wedding guests, as well as place cards explaining the purpose of our donation.

On the evening of November 8, 2008, I walked happily down the aisle with a bit of lace from my mother’s wedding dress sewn into mine, and one of her brooches pinned to my bouquet. With the color purple (also my mom’s favorite color) integrated into our clothing, flowers, and decorations, we each proudly

donned our purple ribbons throughout the night in honor and loving remembrance of her life.

This past February 15th, on the one year anniversary of her passing, my whole family got together again to commemorate my mother’s life. People brought flowers and memories to share, and still others made additional donations to the Hirshberg Foundation to try and help fight this horrific disease. Though my mother was not able to attend my wedding in person, her spirit and her love was all around us that night.

The 11th Annual LA Cancer Challenge 5/10K & Kids Can Cure Fun Run was held on Sunday, October 26, 2008 at the Veterans Administration Grounds in West Los Angeles. It was a record breaking event for the Foundation, as more than 3500 registered runners (up 29% from 2007) raised more than $545,000 (up 16%). For our 2009 event, to be held on Sunday, October 25, our goal is to raise $600,000 and have 4500 registered participants. Visit www.LACancerChallenge.com for more information.

Each year the Hirshberg Foundation chooses one marathon or half-marathon event in a city outside of Los Angeles for our Training Team to participate in. Team members commit to raising a designated amount of money and are given a web page and a complete fundraising packet with tips, sample solicitation letters, and pledge forms to help them reach their goal. Our program features a 17-week compre-

Birthday to Martin Fung who completed his first 13.1 mile

hensive personalized training program for runners and

race as a 49th birthday present to himself. Further congrat-

walkers of all skill levels, led by Robert Mills, Director of

ulations to other half marathoners Dave Manheim, David

Club 26.2. Training begins each January and includes tips

Marcus, Greg & Toni Simon, Bekki Barkan, and Stuart

from experts on injury prevention, nutrition, form and

Wiston. A special thanks to Doug Atkin for coordinating

technique. Virtual training is also available.

In 2008, our team headed to Music City - Nashville, Tennessee to participate in the Country Music Marathon & Half Marathon. With 50 bands playing live on 28 entertainment stages, hundreds of cheerleaders and thousands of spectators on the course, the 2008 Team had a blast and enjoyed the southern hospitality that Nashville offered. Congratulations to Lisa Flashner and Apryl Krakovsky for completing the full marathon with grace! Congratulations and Happy

our hotel stay and being our resident “expert� on all things Nashville.

In May 2009, our team will be heading to the Santa Barbara Wine Country Half Marathon for a scenic journey on a 13.1 mile course through the Santa Ynez Valley bordered by the Sierra Madre Mountains and the Pacific Ocean. All individual participants are responsible for raising $2,500 in pledges prior to the marathon to support the Hirshberg Foundation for Pancreatic Cancer Research. To support our 2009 team or learn more, please visit www.marathon.kintera.org.

Events Benefitting the Hirshberg Foundation This past year many individuals hosted an event to benefit the Hirshberg Foundation for Pancreatic Cancer Research. From tennis and golf tournaments, to concerts and luaus, each event provided a meaningful way to raise awareness and necessary funds for research. We are truly grateful for the support, hard work and dedication of those who made these events possible. To learn more about hosting a fundraising event in support of The Hirshberg Foundation, please visit our website or contact us at 310-473-5121.

Spotlight Events Robert J. Paroli Memorial Tennis Tournament August 17, 2008 Bar Mitzvah Project in memory of Ethan’s grandfather, Robert “My grandfather was a larger than life figure in his community in the Bay Area. He was constantly involved with charitable organizations and fundraising missions, often setting up golf tournaments to raise money for different causes. It would be a true meaningful mitzvah for me to raise money and awareness for a terribly underfunded disease that at this time does not offer the same hope of survival as other cancers.” – Ethan Blank

CottonFest Bluegrass Festival September 27, 2008 In memory of Cotton Raper “Those people that knew my Dad called him Cotton, due to his blonde hair. Cotton raised a family of singers and musicians, so we decided to plan a music festival in his memory. Cotton Fest is held each year on our 17 acre private property in Etowah, Tennessee. We have bands playing mainly Bluegrass, Contemporary Bluegrass, and Southern Gospel Music. I am eternally grateful that there exists a foundation of hope for all those like Doyle and Cotton. This was my way of healing...knowing that their life and their fight will continue.”

– Ronnie Raper

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

2009 EVENT CALENDAR October 25, 2009

12th Annual L.A. Cancer Challenge Los Angeles, CA www.LACancerChallenge.com

MEMORIAL & TRIBUTE FUND EVENTS 2009

Real Results Fitness 5K Amanda Jordan’s 6th Annual Luau July 26, 2008

Las Vegas, NV paul@realresultsfitness.com

Luau in memory of Jacque, Amanda’s mother

June 26, 2009

Amanda Jordan hosted a luau to raise funds for our foundation. The luau offered food, including the traditional pig roast, hula dancers, live music and games. Her event raised more than $7,200.

Phoenix, AZ

A Night of Texas Hold ‘Em, in Memory of Larry H. Meister mik666@cox.net

Kevin Miya Veteran’s Day Golf Classic November 11, 2008

August 2009

Golf Tournament, in memory of Kevin

Grass Valley, CA

Kevin Miya was a Professional Civil Engineer for the City of Pittsburgh who passed away in on February 25, 2008 at the age of 37.

Dal Bon Memorial Golf Tournament www.DalbonMemorial.org or bdalbon@netzero.net September 2009

Cotton Fest Etowah, TN

www.reliancebluegrassband.com October 2009

Kevin Miya Golf Tournament Pittsburg, CA pittraffic@yahoo.com

HIRSHBERG FOUNDATION FOR PANCREATIC CANCER RESEARCH FOUNDATION Newsletter 2009

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