UCLA Agi Hirshberg Center for Pancreatic Diseases 2015 Report

UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES ACTIVITY SUMMARY 2015 DAVID GEFFEN SCHOOL OF MEDICINE AT UCLA

UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

As the founder of the Hirshberg Foundation for Pancreatic Cancer Research, Agi Hirshberg has, for nearly 20 years, had a profound effect on pancreatic cancer research, education, and patient care worldwide. From its inception, the Hirshberg Foundation has greatly elevated UCLA’s contributions to the field, supporting the work of numerous physician-scientists.

With the naming of the UCLA Agi Hirshberg Center for Pancreatic Diseases in February 2015, the Hirshberg Foundation continues to advance UCLA’s multidisciplinary approach to evaluating and treating patients with pancreatic diseases, conducting leading-edge research, and training the next generation of pancreatic disease experts. Some of these achievements are outlined below.

RONALD S. HIRSHBERG TRANSLATIONAL PANCREATIC CANCER LABORATORY Under the direction of Guido Eibl, M.D., Professor in the Department of Surgery at the David Geffen School of Medicine at UCLA, the Ronald S. Hirshberg Translational Pancreatic Cancer Laboratory is at the forefront of research aimed at identifying and understanding the causes and risk factors of pancreatic cancer, facilitating its early detection, and testing preventative and therapeutic treatments. Over the past 15 years, tremendous progress has been made in the laboratory and in the field as a whole in investigating the biology of pancreatic cancer, examining its underlying risk factors, and trying novel therapeutic and preventive strategies. Dr. Eibl emphasizes that the Hirshberg Foundation’s support has been crucial to these advancements.

Funding from the Hirshberg Foundation has been instrumental throughout the years in enabling Dr. Eibl to begin projects and obtain the necessary preliminary data that allows his team to submit competitive grant applications to Federal funding agencies. As a result, Dr. Eibl has secured multiyear grants from the National Institutes of Health (NIH) and has been funded directly by three five-year grants from the National Cancer Institute. His team’s research has so far resulted in more than 80 peer-reviewed scientific articles.

Over the past year, the Hirshberg Fund has aided Dr. Eibl’s investigation of the link between obesity, inflammation, and pancreatic cancer. His team found that a diet high in fats and calories increased the risk of developing pancreatic cancer in a genetically modified animal model. His team is currently conducting additional studies using animal models and primary cell cultures to examine the mechanistic links between obesity and pancreatic cancer. Although the project has received funding from a Program Project Grant from the National Cancer Institute, Division of Cancer Prevention, the research is extremely costly and these funds are not sufficient to complete the required experiments. Support from the Hirshberg Fund has been crucial to filling this gap.

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

Additionally, Hirshberg funding subsidizes one laboratory technician, who is instrumental in carrying out current lab experiments. The funding also has enabled members of the laboratory to travel to scientific conferences in the United States. These conferences are vital opportunities for Dr. Eibl’s team to present data and communicate with other researchers, contributing to the larger field of pancreatic cancer research and to lab members’ career development. Dr. Eibl and members of his laboratory are immensely grateful for the Hirshberg Foundation’s ongoing support.

UCLA PANCREAS TISSUE BANK Under the direction of David Dawson M.D., Ph.D., Associate Professor in the Department of Pathology and Laboratory Medicine and the Division of Surgical Pathology at the David Geffen School of Medicine at UCLA, the UCLA Pancreas Tissue Bank (PTB) continues to accrue and manage a repository of high-quality archival pancreas tissues and tumors that are made available to researchers for the purpose of facilitating basic and translational research in pancreatic diseases. Support from the Hirshberg Fund covers the expenses of collecting and maintaining the samples and allows PTB resources to be distributed to investigators at little to no cost.

Additionally, it helps with storing samples and maintaining the computer system that holds the clinical pathologic information on patients from whom tissues have been collected.

Over the past decade, support from the Hirshberg Foundation has allowed Dr. Dawson to provide essential resources for pancreatic cancer-focused investigators at UCLA and to collaborate with them on such tasks as the pathologic assessment of tissues and statistical analysis. For example, Dr. Dawson has recently evaluated tissues from animal models tested by Dr. Eibl and drew conclusions on various interventions. Dr. Dawson is currently working with Anna Gukovskaya, Ph.D., Professor in the Division of Digestive Diseases, Department of Medicine at the David Geffen School of Medicine at UCLA. They are studying different markers of autophagy – the natural mechanism that disassembles unnecessary or dysfunctional cellular components – in pancreatic cancer. The PTB played a crucial role in Dr. Gukovskaya’s securing of NIH funding for this research.

The Hirshberg Foundation also supports Dr. Dawson’s work with other UCLA investigators, who are not pancreatic cancer researchers but work on molecules or signaling pathways for which there may be an interface with pancreatic cancer. He is frequently approached by investigators who ask him to evaluate the expression of their markers in pancreatic tissues. In some instances, these projects have turned into full-blown studies of pancreatic cancer that otherwise would not have taken place.

Dr. Dawson’s collaborations expand beyond UCLA. He has recently worked with Matthias Hebrok, Ph.D., Director of the Diabetes Center at the University of California, San Francisco, who has

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

a strong interest in pancreatic cancer and is looking at a variety of transcription factors involved in the development and progression of the disease. Dr. Dawson has assisted him in developing tissue microarrays, which enable the evaluation of hundreds of tissue samples on a single slide. They are using the slides to assess the relevance of markers found in Dr. Hebrok’s animal models to human tissue and seeking to draw correlations in human patients.

Dr. Dawson often works directly with medical residents, training the next generation of medical scientists. Over the past year and a half, he has worked closely with two surgical pathology fellows in the lab of Timothy Donahue, M.D., Associate Professor in the Division of General Surgery and the Department of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA. They have created tissue microarrays of more than 100 patient tissue samples, identifying markers in tumors that arise where the pancreas, bile duct, and duodenum meet. The tumors were of interest because they have two discrete patterns of outcomes for patients. Some reflect a pattern similar to epithelial tumors and behave like typical pancreatic cancers, which are very aggressive. This work led to abstracts that the fellows presented at the United States and Canadian Academy of Pathology annual meeting.

Dr. Dawson is profoundly grateful for funding from the Hirshberg Foundation and for the Foundation’s recognition that a strong pancreas tissue bank is key to UCLA’s ability to further the understanding of pancreatic cancer. This support ensures that pancreas tissue samples are not simply placed in a general biobank, but are organized effectively and made available to researchers in a timely manner.

The research being done in the PTB has many implications for future pancreatic cancer patients, from adopting certain biomarkers that can be used to make treatment decisions, to allowing doctors to give patients more information about their tumors and what they may be able to expect in terms of clinical behavior.

PSYCHOSOCIAL CARE VIA SIMMS/MANN Under the direction of Anne Coscarelli, Ph.D., Adjunct Professor of Medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA and Clinical Professor in the UCLA Department of Psychology, the Simms/Mann–UCLA Center for Integrative Oncology last year provided individualized medical and psychosocial interventions to more than 2,000 patients and families dealing with various cancer diagnoses and treatments, including pancreatic cancer. Support from the Hirshberg Foundation was essential to this achievement.

Over the past year, the Hirshberg Fund contributed to the success of the Simms/Mann team in strengthening its relationship with UCLA physicians and other medical team members who provide care to patients with pancreatic cancer. Systematic outreach included attending surgical clinics and maintaining a presence in the medical oncology offices that provide pancreatic cancer treatments.

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

These efforts helped ensure that patients with pancreatic cancer and their families were aware of and able to take advantage of the Center’s many offerings, most of which are available at no cost to them. These include visits with licensed psychologists and oncology social workers who offer individual and family counseling, and appointments with the Center’s psychiatrist who evaluates patients and their families and assesses their need for medications that may help them with sleep disorders, depression, anxiety, fatigue, and other conditions facing those affected by pancreatic cancer. Additionally, the Center’s interfaith chaplain is available for patients and families who seek spiritual support.

The Hirshberg Fund also assists the Center with such offerings as the monthly lecture series, “Insights into Cancer,” which allows patients with pancreatic cancer and their families to connect with the larger community of physicians focused on cancer research. The Center’s support groups and workshops on topics such as mindfulness meditation, art therapy, and qigong enable patients to meet others who are being treated for cancer, while the Reflections Boutique aids with appearance issues caused by cancer and its treatment. Finally, the Center provides an extensive informational newsletter and online resources. Dr. Coscarelli is grateful for the Hirshberg Foundation’s partnership in all of these endeavors to offer holistic treatment to patients and families affected by pancreatic cancer.

HIRSHBERG FOUNDATION SEED GRANT PROGRAM The Hirshberg Foundation’s Seed Grant Program continues to be a key factor in advancing pancreatic cancer research around the world. Launched more than a decade ago, the Program’s more than $5 million in seed grants to more than 60 awardees has generated more than $65 million in additional funding from the NIH and other agencies to support research involving the molecular mechanisms of pancreatic cancer, early diagnosis, surgical and chemotherapeutic treatments, psychosocial approaches to management, and prevention strategies.

Support from the Hirshberg Fund allows the office of Bill Go, M.D., Distinguished Professor, Department of Medicine, Division of Digestive Diseases/Gastroenterology at the David Geffen School of Medicine at UCLA, and Director, UCLA Center for Excellence in Pancreatic Diseases, to successfully manage the administration of the Hirshberg Foundation Seed Grant Program, including providing responses to research-related queries about the seed grants. Dr. Go’s office coordinates the research activities of programs conducting pancreatic research at UCLA with NIH support, currently including 2 P01s, 1 P30, 1 U01 and other R01 and R21 grants. Dr. Go’s office also interacts with current and previous seed grant awardees on their progress reports and accomplishments. The Hirshberg Fund partially supports the salary and benefits of Dr. Go’s administrative assistant, who plays a key role in coordinating these efforts.

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

UCLA SEED GRANT RECIPIENTS The Hirshberg Fund supported five 2014-2015 Hirshberg Foundation Seed Grant recipients from UCLA working on pancreatic cancer and related research. Below are brief updates on their projects.

William Gelbart, Ph.D. Armored Self-Replicating Genes as Delivery Systems for Early Pancreatic Cancer Detection

by Magnetic Resonance Molecular Imaging.

The team of Dr. Gelbart, Distinguished Professor of Chemistry and Biochemistry at UCLA, has made significant progress toward their goal of demonstrating a new and improved strategy for enhancing MRI imaging contrast in targeted cells, thereby facilitating an earlier detection of cancer. By locally introducing large quantities of ferritin, the protein that stores iron in cells, the team can exploit the fact that local iron concentrations provide the desired enhancement of MRI contrast. Instead of directly introducing iron nanoparticles (which have biocompatibility issues) or ferritin genes in DNA form (which cannot be easily packaged for protection), the team uses ferritin genes in RNA form, which can be efficiently packaged into virus-like particles that both protect them and target them to cancer cells. Further, the RNA genes are in a self-replicating form that assures a higher level of ferritin expression than could otherwise be achieved.

Preliminary in vivo studies in mice show a clear MRI contrast enhancement in tissue that has been injected with self-replicating ferritin genes. The next step is to package these genes in viruslike particles, or protective shells, which have been modified with antibodies against antigens known to be overexpressed in pancreatic cancer cells, and to thereby “light up” these cells in MRI imaging.

Wai-Nang Paul Lee, M.D. Metabolic Profile of Gemcitabine Resistance in Pancreatic Cancer.

Dr. Lee, Professor of Pediatrics in the Division of Pediatric Endocrinology and Metabolism at the David Geffen School of Medicine at UCLA, received support for his research on the application of stable isotopes in the study of metabolic changes in pancreatic ductal carcinoma and its drug resistance. This support helps fill important gaps in Dr. Lee’s NIH funding. As a result of this research, Dr. Lee has developed a biomarker of cancer metabolism, a general method for measuring protein turnover in cells that allows the cancer cells to proliferate, and a new understanding of energy substrate metabolism as a hybrid engine that uses glucose as the primary fuel. Dr. Lee hopes that these accomplishments will help him obtain future NIH grants to continue his research on tracer-based metabolomics.

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

She-Hi Liu Development of a Potent Synthetic Reporter System for Earlier Detection, Accurate Quantification, and Precise Localization of Pancreatic Cancer.

Mr. Liu’s research team has demonstrated that GLuc, a naturally secreted protein, is a highly sensitive synthetic biomarker when it is expressed in human pancreatic cancer cells (PDAC). The team conducted an in vivo study with a model implanted with PDAC expressing GLuc and found that GLuc can be detected in the blood as early as two days after implantation, even though no visible tumors were observed. In combination with a PDAC-specific promoter, they developed a novel approach for highly sensitive and specific detection of early PDAC, which will be life-saving for high-risk patients who otherwise will develop unresectable, metastatic PDAC disease.

Qing-Yi Lu, Ph.D. A Pilot Study on the Anti-Hyperglycemic and Anti-Tumor Effects of Loquat Leaf Extract.

Dr. Lu’s research team has identified a new pharmacological activity of loquat leaf extract in suppressing the growth of pancreatic cancer cells and inducing apoptosis, or programmed cell death. They also have linked loquat leaf-induced p-AMPK deactivation to the regulation of tumor cell suppression and regulation of glucose metabolism. These studies provided preliminary results for further in-depth investigations of the anti-tumor and anti-hyperglycemic mechanism of loquat leaves.

Heloisa Soares, M.D. Cross Talk Between PI3K/mTOR and MEK/ERK. Pancreatic cancer is typically caused by a series of gene mutations. Therefore, drug therapies that target affected genes are very promising. However, early clinical studies with some of the available target therapies failed to show substantial improvements in patients’ survival. The seed grant support allowed Dr. Soares’ group to identify possible mechanisms of resistance to target therapies. This work provides the rationale for the development of better treatment strategies for pancreatic cancer. Since receiving the Hirshberg Foundation Seed Grant, Dr. Soares was appointed to the faculty of the Moffitt Medical Center, where she continues her research.

We look forward to seeing the work and providing updates on Drs. Stergios Katsiougiannis, Zhao Li, Huan Meng, Alice Soragni, and Ken Herrmann, who were among the 2015-2016 Hirshberg Foundation Seed Grant Recipients.

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UCLA AGI HIRSHBERG CENTER FOR PANCREATIC DISEASES David Geffen School of Medicine at UCLA

THE HIRSHBERG FOUNDATION’S PAST, PRESENT, AND FUTURE PARTNERSHIP The UCLA Agi Hirshberg Center for Pancreatic Diseases provides a critical hub for advancing pancreatic cancer research and treatment breakthroughs, most recently with the establishment of an Integrated Practice Unit, which breaks down traditional divisions and brings together in a shared space experts in surgery, oncology, pathology, radiology, and more. The benefits of this approach are wide-ranging, from granting patients ease of access to multiple providers to allowing physician-scientists improved opportunities for collaborations on treatment and research. This innovation is merely one example of how the Hirshberg Foundation will continue to improve the lives of patients in Southern California and around the world.

Support from the Hirshberg Foundation has been instrumental in establishing UCLA as a leader in pancreatic cancer treatment, research, and education and in helping to continually build on this legacy. As evidenced by this report, the impact of the Hirshberg Foundation’s support in fighting pancreatic cancer worldwide cannot be overstated. Our patients, physicians, researchers, and staff are profoundly grateful for this partnership.

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