Pancreatic Cancer

Current Projects
Vinod P. Balachandran, MD

Despite our best current treatments, 95% of patients with pancreatic cancer, including those at the earliest stages, die within 5 years of diagnosis. By 2020, pancreatic cancer will become the second leading cause of cancer-related death in the U.S., and new therapies are urgently needed. T cells are highly specialized cells of the immune system designed to protect the human body from infections and cancer. Very few T cells recognize pancreatic cancer; however, recent work showed that these T cells play a very important role in controlling the spread of pancreatic cancer. Patients whose tumors have higher proportions of T cells survived over 3-times longer than patients who did not. Vinod’s group has unique access to these extremely rare patients that survived on average 6 years with pancreatic cancer and whose tumors have 12-times as many activated T cells as patients who have more typical poor outcomes. He has discovered that their exceptional survival is linked to T cells recognizing novel cancer proteins or neoantigens that make these cancers resemble infections. His research will focus on understanding these unique cancer proteins in long-term survivors, with the goal of developing novel immunotherapies to treat all patients with pancreatic cancer. He is now testing neoantigens as cancer vaccines in a Phase I clinical trial. 

In addition, Vinod is exploring another strategy to activate the immune system in pancreatic cancers. He hypothesizes that a new type of immune cell, ILC2s (group 2 innate lymphoid cells) can be therapeutically activated to promote anti-tumor immunity. His strategy will test the combination of recombinant interleukin-33 (rIL-33) with checkpoint inhibition (PD-1 blockade), and assess activation of ILCs and restriction of tumor growth. He aims to rapidly translate these findings into a first-in-human clinical trial. 

 

Project title: "Recombinant interleukin-33 immunotherapy for pancreatic cancer"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: 1440 Foundation Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Steven D. Leach, MD, and Jedd D. Wolchok, MD, PhD
Cancer Type: Pancreatic
Research Area: Immunotherapy
Robert S. Banh, PhD

Dr. Banh is focusing on the role of sensory neurons in promoting pancreatic tumor growth. Interestingly, most pancreatic tumors display increased number of sensory nerves, which cause pain in patients. Dr. Banh hypothesizes that sensory neurons may metabolically support pancreatic tumor growth in nutrient poor environments by directly releasing nutrients or by changing the cancer’s nutritional demands. Elucidating this crosstalk in regulation and function will help gain insight into the contributions of neurons on the development of pancreatic tumors, and potentially other cancers, with the ultimate goal of identifying novel treatment strategies.

 

Project title: "Metabolic contribution of sensory neurons to pancreatic tumorigenesis and serine metabolism, via peripheral axons"
Institution: New York University School of Medicine
Named Award: Merck Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Alec C. Kimmelman, MD, PhD, and Michael Pacold, MD, PhD
Cancer Type: Pancreatic
Research Area: Biochemistry
Caroline Bartman, PhD

Dr. Bartman studies the unique nutritional requirements of cancer cells compared to healthy tissues. Dr. Bartman will use mass spectrometry measurements of labeled nutrients and computational modeling to quantify metabolic fluctuations in both pancreatic cancer cells and healthy organs in mice. Since altered metabolism is a hallmark of cancer cells, systematically mapping these metabolic changes may guide drug development to rationally target cancer while sparing healthy cells.

 
Project title: "Systems analysis of in vivo tumor and stromal cell metabolism in pancreatic ductal adenocarcinoma"
Institution: Princeton University
Named Award: The Mark Foundation for Cancer Research Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Joshua Rabinowitz, MD, PhD
Cancer Type: Pancreatic
Research Area: Systems Biology
Luisa F. Escobar-Hoyos, PhD

Current pancreatic cancer chemotherapies are not effective, and targeted therapies are only applicable in about 5% of cases. Furthermore, pancreatic cancers cause immune cell stress, limiting the success of immunotherapies in this disease. Using animal models and tumor samples from pancreatic cancer patients, Dr. Escobar-Hoyos has discovered that changes in RNA splicing, a process that controls protein diversity in cells, are crucial for pancreatic cancer development, therapy resistance, and disruption of anti-tumor immunity. The proposed project will dissect the molecular role of RNA splicing in pancreatic cancer, which likely drives the disease's lethality. She seeks to develop a novel anti-RNA splicing therapy with dual action-a targeted therapy against tumor cells coupled with an immunotherapy to restore immune cell anti-tumor activity-to more effectively treat pancreatic cancer patients.

Project title: "Understanding RNA splicing in tumor-cell adaptation and anti-tumor immunity"
Institution: Yale University
Award Program: Innovator
Cancer Type: Breast, Lung, Pancreatic
Research Area: Cell Biology
Nir Hananya, PhD

Dr. Hananya is investigating a component of the DNA repair machinery termed protein ADP-ribosylation. Our cells are constantly exposed to chemicals and electromagnetic radiation harmful to DNA. Since the integrity of our genetic material is critical, cells have evolved a variety of mechanisms to repair lesions in the DNA. But defects in these DNA repair pathways caused by genetic mutations can lead to genomic instability, which drives cancer development. Dr. Hananya is utilizing chemical biology to study ADP-ribosylation and to delineate its role in DNA repair. The research will provide vital information regarding cancer genesis and progression and will contribute to the development of new therapies.

Project title: The roles of histone ADP-ribosylation in DNA damage response
Institution: Princeton University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Tom Muir, PhD
Cancer Type: Pancreatic, All Cancers
Research Area: Chromatin Biology
Whitney Johnson, PhD

Dr. Johnson is studying how genome rearrangements occur in cancer, using artificial pancreatic cancer organoids—clusters of cells that act as a model system. Cancer cells have unstable genomes that mutate and rearrange at a high rate compared to normal cells. Ultimately, Dr. Johnson hopes to understand how genome instability may be exploited to improve cancer treatments, including immunotherapy.

 

Project title: "Using organoid cancer models to identify genome catastrophe mechanisms"
Institution: Dana-Farber Cancer Institute
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David Pellman, MD
Cancer Type: Pancreatic, All Cancers
Research Area: Cell Biology
Leeat Keren, PhD

Dr. Keren is combining novel imaging methods with advanced computational analysis, artificial intelligence, and clinical collaborations to investigate how cells within the tumor microenvironment act as a system. She will apply multiplexed imaging and state-of-the-art image analyses to comprehensively characterize cancerous lesions in situ and functionally relate these features to system-level mechanisms such as immune evasion, tumor progression, metastasis, and response to therapy. The ultimate goal is to achieve in-depth understanding of the cancer process to contribute to the development of personalized treatments and diagnostics.

Project title: "Studying the tumor immune microenvironment in pancreatic cancer using multiplexed imaging"
Institution: Weizmann Institute of Science
Named Award: CRIS Cancer Foundation Breakthrough Scientist
Award Program: Dale Frey Scientist
Cancer Type: Pancreatic
Research Area: Systems Biology
Jamie Lahvic, PhD

Dr. Lahvic is investigating how neighboring normal cells will try to impede the growth of cancer cells, and how a tumor escapes these controls. Dr. Lahvic aims to understand the genetic predispositions to cancer and find clues to a new way of preventing and treating cancer: activation of normal cells to directly fight a nearby tumor. While this work could hold relevance for all carcinomas, she is focusing on Ras mutations, which are especially common in pancreatic and colon cancers.

Project title: "Uncovering cell non-autonomous mechanisms of tumor suppression"
Institution: University of California, Berkeley
Named Award: The Mark Foundation for Cancer Research Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Iswar Hariharan, MBBS, PhD
Cancer Type: Pancreatic, All Cancers
Research Area: Cancer Genetics
Monica E. McCallum, PhD

Dr. McCallum studies a compound, called alanosine, which exhibits anti-cancer activity against cells from sarcomas, mesothelioma, and pancreatic cancer. This compound is produced by a soil-dwelling bacterium. She seeks to elucidate how bacteria produce alanosine. Understanding the genes and enzymes that assemble this molecule will guide the discovery of additional novel chemotherapeutic agents that may be produced by bacteria.

Project title: "Understanding alanosine biosynthesis to discover new cancer chemotherapeutics"
Institution: Harvard University
Award Program: Fellow
Sponsor(s) / Mentor(s): Emily P. Balskus, PhD
Cancer Type: Pancreatic, Sarcoma
Research Area: Biochemistry
Mandar D. Muzumdar, MD

Obesity is a major risk factor for over a dozen cancer types, including pancreatic cancer, the third leading cause of cancer-related death in the United States. Despite the rising prevalence of obesity worldwide, surprisingly little is known about how it promotes cancer development. Using animal models that closely mimic human pancreatic cancer, Dr. Muzumdar showed that obesity could provoke abnormal signals sent by the hormone-producing cells of the pancreas to their neighboring tumor-forming cells. With this project, he aims to understand how these hormones are induced and act to drive cancer formation in obesity. Targeting pancreatic hormone signaling could provide a new approach for the prevention and treatment of pancreatic cancer and other obesity-associated cancers.

Project title: "Targeting endocrine-exocrine signaling in pancreatic ductal adenocarcinoma progression"
Institution: Yale University School of Medicine
Award Program: Innovator
Cancer Type: Pancreatic
Research Area: Carcinogenesis
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