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
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
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
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
Joseph D. Mancias, MD, PhD

Dr. Mancias is exploring the synergistic interactions between radiation therapy and targeted immunotherapy in patients with pancreatic cancer (pancreatic ductal adenocarcinoma, “PDAC”). While this treatment combination has shown dramatic benefits for patients with certain cancer types, it has been challenging to predict which patients will respond and to determine how to harness the anti-tumor immune cell effects of radiation. Identifying the PDAC radiation-induced antigens will shed light on the interaction between the immune system and radiation and provide the basis for designing effective immunotherapies for patients with pancreatic and other cancers (such as glioblastoma, prostate cancer, breast cancer, lung cancer, head and neck cancers, pediatric cancers).

Project title: “Identifying the pancreatic tumor MHC-I ligandome in response to ionizing radiation for combination radiation-immunotherapy”
Institution: Dana-Farber Cancer Institute
Award Program: Innovator
Cancer Type: Pancreatic
Research Area: Tumor Immunology
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
Jasper E. Neggers, PhD

Dr. Neggers is focusing on validating a new drug target for pancreatic cancer. Using large-scale genetic screening, Dr. Neggers discovered that a subset of cancers, including over 50% of pancreatic cancers, selectively require the VPS4A gene to proliferate and grow. When VPS4A is turned off, the cells stop dividing and die. He will study this vulnerability in clinically relevant patient-derived and mouse models of pancreatic cancer to understand how it functions. His research may help confirm whether this gene should be pursued as a significant drug target.

 
Project title: "Validation of VPS4A as a synthetic lethal target in cancers with VPS4B loss on chromosome 18q"
Institution: Dana-Farber Cancer Institute
Award Program: Fellow
Sponsor(s) / Mentor(s): Andrew J. Aguirre, MD, PhD, and Todd R. Golub, MD
Cancer Type: Pancreatic, Sarcoma, All Cancers
Research Area: Cell Biology
Michael E. Pacold, MD, PhD

Oxygen is a double-edged sword in pancreatic cancer biology. Pancreatic cancers require oxygen, but they are amongst the most hypoxic of cancers, with oxygen concentrations as low as 200-fold below atmospheric oxygen concentrations. Pancreatic cancers use oxygen to make molecules critical for their survival and proliferation, but they are also vulnerable to oxidative stress, which is essential for the effectiveness of cancer treatments such as radiation. Dr. Pacold has developed techniques to determine which oxygen-dependent reactions are prioritized by pancreatic cancers and enhanced by radiation treatment, with the goal of identifying new targets that could be used for treating pancreatic and other cancers that are treated with radiation.

Project title: "Tracing molecular oxygen in pancreatic cancer"
Institution: New York University Langone Health
Award Program: Innovator
Cancer Type: Pancreatic
Research Area: Biochemistry
Rushika M. Perera, PhD

Cancer cells have a unique ability to rapidly and efficiently remodel their internal composition and metabolic pathways in order to maintain accelerated growth, metastasize and resist anti-cancer therapies. The lysosome, an organelle in the cell that degrades cellular debris, has the ability to control a cancer cell's adaptability. Through processing and recycling different macromolecules, the lysosome serves as an important source of fuel for cancer cell growth and spare parts for remodeling the cell. Dr. Perera is focusing on pancreatic ductal adenocarcinoma (PDAC), which is highly dependent on lysosomes for growth. She has characterized cancer-specific lysosomal proteins and showed that these proteins confer PDAC cells with two key properties: the ability to rapidly repair their membranes in the face of sustained mechanical and chemical insults, in order to maximize nutrient uptake, and to alter their cell membrane composition to evade recognition by the host immune system. Collectively, these results suggest largely unexplored roles for the lysosome in PDAC and highlight novel vulnerabilities that could be exploited therapeutically.

Project title: "Mechanisms of cellular transformation at the single organelle level"
Institution: University of California, San Francisco
Named Award: Nadia's Gift Foundation Innovator
Award Program: Innovator
Cancer Type: Pancreatic
Research Area: Animal Models/Mouse Models
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