UCLA Agi Hirshberg Center for Pancreatic Diseases Activity Summary 2022

Basic and Translational Pancreas Research, and Program Director of the Gastroenterology Fellowship Program at Cedars-Sinai Medical Center. The main scientific focus of the program is the study of the impact of obesity on pancreatic cancer development using cell culture and scientific models. The program investigates the impact of statins and metformin, both FDA-approved drugs, on pancreatic cancer development and progression. To date, the researchers’ principal finding is that at relatively high concentrations, metformin and lipophilic statins impede pancreatic cancer development in a genetically engineered scientific model of pancreatic cancer. At lower concentrations, the combination of metformin and statins also inhibited the formation of pancreatic cancer precursor lesions in preclinical models. These results may have important translational significance.

Dr. Eibl continues to have a highly productive collaboration with Dr. Rozengurt and his team. Together, they investigated the impact of dasatinib and trametinib, approved by the FDA for the treatment of certain leukemias and melanoma, respectively, on pancreatic cancer growth. Dr. Eibl found that while each individual drug has little to no effect on pancreatic cancer growth in scientific models, the combination of dasatinib and trametinib almost completely inhibited cancer growth. The team discovered the mechanism that underlies the combination effect through cell culture studies. These very intriguing findings were published in MolecularCancerTherapeutics, a high-impact, peer-reviewed journal. The team has applied for a grant that will allow them to further pursue this project through the National Cancer Institute.

Another collaboration with Dr. Rozengurt investigates the impact of chronic stress in combination with obesity on pancreatic cancer development and progression. Funded by the National Cancer Institute, this two-year grant will test the hypothesis that chronic social isolation stress will exacerbate the tumor-promoting effects of obesity in genetically engineered scientific models predisposed to pancreatic cancer.

In collaboration with the Metabolic Epidemiology Branch of the Division of Cancer Epidemiology & Genetics, National Cancer Institute, Dr. Eibl was involved in a study of the correlation of body mass index (BMI) trajectories across adult life spans and pancreatic cancer risk. High BMI and BMI trajectories that result in overweight or obesity during adulthood were positively associated with pancreatic cancer in scientific models, with stronger associations among those with early onset adiposity and males. The highest risk category was seen in patients with an overweight-to-severe obesity trajectory.

In addition to the aforementioned article in MolecularCancerTherapeutics, Dr. Eibl published in two other leading journals in 2022. Studies investigating the effects of statins on inflammatory responses in the pancreas and the formation of early pancreatic cancer precursor lesions were published in GastroHepAdvances. This paper was highlighted as one of the top basic science articles of 2022 by the American Gastroenterological Association. The epidemiological project looking at the BMI trajectories and pancreatic cancer risk was published in JNCICancerSpectrum

UCLA Agi Hirshberg Center for Pancreatic Diseases Activity Summary 2022

Dr. Eibl’s mentorship and guidance benefits the research of Yaroslav Teper, Ph.D., an assistant project scientist in the Hirshberg Lab. Dr. Teper continues to work on a project funded by a seed grant from the Hirshberg Foundation, which will develop more refined scientific models of diet-induced obesity and pancreatic cancer. A new postdoctoral fellow, Xiaoying Sun, M.D., Ph.D., started in 2022. Her time and effort are shared between the laboratories of Drs. Rozengurt and Eibl.

Dr. Eibl notes that although the Hirshberg Lab was productive during the pandemic, there continued to be challenges in 2022 posed by supply chain issues and staff shortages in several core facilities at UCLA. Dr. Eibl is therefore especially thankful for the crucial support of the Hirshberg Foundation, which enabled his lab to secure funding from the National Institutes of Health (NIH).

UCLA Pancreas Tissue Bank

David Dawson, M.D., Ph.D., Professor of Pathology in the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, oversees the UCLA Pancreas Tissue Bank, which continues its successful accrual and distribution of human pancreas specimens in support of basic and translational pancreatic cancer and disease research. These resources include viable, snap-frozen, and fixed tissues gathered both prospectively and from archival clinical materials and strengthened through the availability of de-identified clinicopathologic information, including treatment and outcomes data.

In addition to providing tissue resources, Dr. Dawson supports pancreas research colleagues at UCLA and many other institutions through histology services and histopathologic review. The bank continues to adapt to evolving research demands and is currently shifting toward a greater focus on banking viable cell samples and generating high-quality live tissue slices derived directly from patient samples or xenografts, made possible through its recent investment in a vibrating microtome used for tissue sectioning.

Essential funding from the Hirshberg Foundation enables Dr. Dawson to provide tissue samples and pathology consultative services free of charge to collaborators, thus resulting in a multiplier effect, as these resources benefit the work of the wider pancreatic research community. Most notably, Dr. Dawson serves as the primary investigator for the pathology core of the UC Pancreatic Cancer Consortium, which plans to submit a new Specialized Programs of Research Excellence (SPORE) application to the NIH this spring. If funded, this SPORE will enable tremendous growth in pancreatic cancer research at UCLA and other UC sites. The Hirshberg Foundation has had an integral role in establishing the biobanking infrastructure that is a necessary part of any SPORE application.

Over the past year, Dr. Dawson has continued to support projects led by Dr. Donahue. Their current research addresses the interplay of KRAS signaling, metabolism, inflammation, and immune response in pancreatic cancer, and potential therapeutic opportunities linked to these observations. Dr. Dawson also provided ongoing assistance with clinical trials led by Zev Wainberg, M.D., Professor of Medicine and Co-Director of the UCLA Gastrointestinal Oncology Program, exploring neoadjuvant chemotherapy in combination with drugs designed to enhance the immune response to tumors. With seed grant recipient Jason Link, Ph.D., Division of Surgical

UCLA Agi Hirshberg Center for Pancreatic Diseases Activity Summary 2022

Oncology, and Associate Adjunct Professor, Department of Surgery, David Geffen School of Medicine at UCLA, Dr. Dawson is analyzing tissue samples from these patients before and after treatment through a variety of approaches, including multiplex immunohistochemistry, spatial transcriptomics, and digital pathology utilizing artificial intelligence/machine learning approaches. He also is collaborating with Heather Christofk, Ph.D., Professor of Biological Chemistry at the David Geffen School of Medicine at UCLA, Associate Director of Basic and Translational Research at the UCLA Jonsson Comprehensive Cancer Center, and Co-Director of the UCLA Metabolomics Center, on mechanistic studies of the role of specific dietary fats in driving tumor initiation and progression in scientific models of pancreatic cancer.

Dr. Dawson’s various projects with researchers outside of UCLA include partnerships with the University of California, San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of California, San Francisco; and Mayo Clinic. Without the Hirshberg Foundation’s support, Dr. Dawson would be unable to provide samples and analyses for these endeavors. He is deeply appreciative for the flexibility to contribute to these crucial investigations, and he was honored to participate in the Hirshberg Foundation’s 25th anniversary video.

Psychosocial Care via the Simms/Mann-UCLA Center for Integrative Oncology

Under the direction of Barbara Jagels, R.N., M.H.A., C.P.H.Q., Senior Director of Cancer Services at UCLA Health and Interim Director of the Simms/Mann Center for Integrative Oncology, and Kauser Ahmed, Ph.D., Darcie Denkert Notkin Director of Psychosocial Oncology, the Simms/Mann Center provides crucial psychosocial treatment for patients with pancreatic cancer and their families. As the world moves beyond some of the more restrictive aspects of the pandemic, the Simms/Mann Center has increased its in-person offerings while still catering to those who want or need to be treated remotely.

The Simms/Mann Center has expanded the roles of several staff members to focus even more resources on the treatment of pancreatic cancer. Deana Lozano, M.B.A., an administrator for the Simms/Mann-UCLA Center for Integrative Oncology, and Aletta Deranteriassian, an administrative specialist for surgical oncology, are working with the care team at the Simms/Mann Center to implement a distress screening tool in the clinic. This system will help staff monitor and recognize distress levels in pancreatic cancer patients and allow the team to take appropriate action in a timely manner. This new tool augments the effective psychosocial assistance given to pancreatic cancer patients, led by Elizabeth Cleary, Ph.D., and Greg Flaxman, L.C.S.W., M.P.H. Dr. Cleary continues to serve patients in a remote capacity, while Flaxman remains facilitator of the mindfulness meditation group, in addition to his clinical social worker responsibilities in the Hirshberg Center IPU.

On average, each pancreatic cancer patient participates in five interactions with the Simms/Mann Center during the course of their treatment. While this number is down from the previous year, it still represents a level of follow up uncommon in the field, and serves as a testament to the staff’s dedication to each individual, beginning with the diagnosis and continuing through each subsequent step. Overall pancreatic cancer patient

UCLA Agi Hirshberg Center for Pancreatic Diseases Activity Summary 2022

interactions increased six percent from 2021 to 2022, continuing a trend of expanded support for this patient population. The Simms/Mann Center now provides services to every UCLA hematology/oncology clinic in the Southern California region, further expanding the number of patients who have access to this vital care.

Virtual workshops were popular with pancreatic cancer patients, including a new offering, Communication in the Cancer Context: Talking with Your Medical Team, Family, and Others Who Care. Another new initiative is the Advanced Cancer Orientation and Family Check-In for patients newly diagnosed with pancreatic cancer, led by Jenny Tran, Ph.D., and Danielle Siegel, L.C.S.W. This collaboration helps connect patients to their support teams, communicating their needs and addressing complex symptoms earlier in the process. This has led to decreased emergency department visits, decreased intensive care unit stays, and more appropriately timed referrals to hospice care. Dr. Tran also presented at the Hirshberg Foundation Symposium in March 2022.

Jagels, Dr. Ahmed, and the entire staff of the Simms/Mann Center are extremely appreciative of the philanthropy that the Hirshberg Foundation provides to the center, particularly in the way it increases their ability to treat patients with pancreatic cancer. The funding from the foundation affords the Simms/Mann Center the flexibility and resources it needs to devote so much of its energy to treating this vulnerable, yet resilient, patient population.

Ronald S. Hirshberg Chair in Translational Pancreatic Cancer Research

Dr. J. Enrique Rozengurt, Distinguished Professor of Medicine at the David Geffen School of Medicine at UCLA, Chief of Research for the UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, and Director of CURE: the UCLA Digestive Diseases Research Core Center (CURE: DDRCC), is a pioneer in the area of signal transduction and cell growth regulation. Support from the chair enables Dr. Rozengurt and his team to advance their efforts to identify novel targets, approaches, and biomarkers for the prevention and treatment of pancreatic cancer. Their continued research on metformin and statins as potential inhibitors of pancreatic cancer cell growth has the possibility of rapid translation because these drugs are FDA approved and widely used in the treatment of type 2 diabetes, hypercholesterolemia, and other conditions, including pre-diabetic states. New research has uncovered drug combinations for therapeutic use.

Dr. Rozengurt has continued his research on the pro-oncogenic protein YAP, which has been identified as a target of the FDA-approved drugs of the statin family, opening a new avenue for preventing and treating pancreatic cancer. Dr. Rozengurt and his colleagues have found that the statins potently block YAP-regulated genes in pancreatic cells and that various statins inhibit the multiplication of pancreatic ductal adenocarcinoma cells—as well as act synergistically with metformin. Ongoing work using human and preclinical pancreatic cell models and a scientific model of pancreatic cancer includes testing whether a low-dose combination of statins with metformin acts additively or synergistically in inhibiting pancreatic cell proliferation and preventing the development of pancreatic cancer. New mechanistic studies discovered that a combination of FDA-approved inhibitors targeting the Src/YAP axis (using the drug dasatinib) and the MEK/ERK pathway (using the drug trametinib) potently inhibited the multiplication of human pancreatic cancer cells. This new discovery, published in the prestigious journal MolecularCancerTherapeutics, expands the group’s chemo-preventive metformin and statin studies to drugs to be considered for the treatment of pancreatic cancer.

UCLA Agi Hirshberg Center for Pancreatic Diseases Activity Summary 2022

Recent publications include scientific articles and reviews in significant medical periodicals, including Cancers; CancerandMetastasisReviews;GastroHepAdvances;JournalofImmunology; and, as mentioned above, MolecularCancerTherapeutics

Dr. Rozengurt, along with Drs. Eibl and Pandol, continues to work on a program grant from the National Cancer Institute. Dr. Rozengurt also receives funds from an existing VA Merit Review Program grant, as well as two new NIH grants, one of which received funding in May 2022. The major goal of this new project is to determine the interaction between chronic stress and obesity in accelerating pancreatic cancer progression using genetically precise scientific models of the disease and to define the mechanisms involved.

Dr. Rozengurt’s work has been cited more than 38,000 times in scientific papers, and he continues to be one of the world’s foremost experts in his field.

Hirshberg Foundation Seed Grant Program

Through 2022, Vay Liang W. Go, M.D., Distinguished Professor of Medicine, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, and Co-Director, UCLA Agi Hirshberg Center for Pancreatic Diseases, managed the Hirshberg Foundation Seed Grant Program in collaboration with the Hirshberg Scientific Advisory Board. The Hirshberg Foundation has awarded 104 seed grants to investigators at medical research institutes around the globe since 2004. The foundation also continues to support Jennifer Carney, M.P.H., who is vital to the operation of the seed grant program.

This spring, Miklos Sahin-Toth, M.D., Ph.D., took over from Dr. Go, who retired. Dr. Sahin-Toth was recruited by UCLA in 2019 and is a professor in the Department of Surgery and editor-in-chief of Pancreatology. He is a leading pancreatic disease researcher and specialist in chronic pancreatitis, and serves as the Garry Shandling Chair in Pancreatic Diseases.

Yaroslav Teper, Ph.D., and Keisuke S. Iwamoto, Ph.D., were the UCLA recipients of seed grant funding in 2021. A valuable member of Dr. Eibl’s team in the Hirshberg Lab, Dr. Teper is using his grant to investigate the link between pancreatic cancer cell development and obesity. His team is in the early stages of producing a scientific model with optimal gene alterations in order to conduct their research, and the process is unfolding according to plan.

Dr. Iwamoto is studying the use of weak electromagnetic fields as a therapy for pancreatic cancer. Bolstered by support from the Hirshberg Foundation seed grant, he and his team have made important strides, including demonstrating that specific electromagnetic field strengths increase the radio sensitivity of pancreatic cancer cell lines while not damaging enteroids (an organoid specific to the digestive tract), an important marker for effective therapy.

Eight deserving scientists were awarded seed grants in 2022, including three researchers from UCLA: Evan Abt, Ph.D.; Alexandra Demcsak, M.D., Ph.D.; and Jason Link, Ph.D.