Pancreatic Cancer

Current Projects
Corina E. Antal, PhD

Dr. Antal [Robert Black Fellow] aims to develop ways to increase the efficacy of pancreatic cancer chemotherapy. The reason for pancreatic cancer drug resistance is the presence of a dense, supportive tissue surrounding the cancer cells. She is using multiple high-throughput approaches to identify and target key genes within this tissue in order to reduce its supportive role. This work will aid in developing therapies to increase the delivery of the chemotherapeutic drugs to the tumor, allowing immune cells to infiltrate the tumor and kill cancer cells.

Project title: "Stromal reprogramming as a therapeutic approach in pancreatic cancer"
Institution: The Salk Institute for Biological Studies
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Ronald M. Evans, PhD
Cancer Type: Pancreatic
Research Area: Drug Discovery
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 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.

Project title: "Defining the evolutionary dynamics and antigen potential of neoantigens for human pancreatic cancer immunotherapy"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: William Raveis Charitable Fund Scientist
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
Julia C. Carnevale, MD

Pancreatic cancer may soon become the second leading cause of cancer deaths in the nation. While many cancers have mutations that can be targeted with specific drugs, historically no such targets had been recognized in pancreatic cancer. This changed recently with the discovery that approximately one of every four pancreatic cancers has a defect in the machinery that repairs DNA damage. For example, some have been found to have mutations in the BRCA genes as well as other similar genes involved in repairing double-strand breaks in DNA. Because BRCA-mutant cancers have impaired DNA damage repair, they rely on backup DNA repair systems to survive. Other tumors with BRCA mutations are particularly vulnerable to certain drugs: having such a mutation is an Achilles' heel for the tumor. If the relevant backup systems in these cells can be identified, we can potentially use these dependencies against the tumors. One example of a backup system, the PARP DNA repair system, is currently being targeted in clinical trials in BRCA-mutant pancreatic cancer. Dr. Carnevale aims to uncover multiple vulnerabilities in these cancers that can be targeted with higher efficacy than PARP inhibitors. There may also be candidates for PARP inhibitor combination therapies to more potently eradicate these tumors and/or avoid the development of resistance. She will use a novel screening technology called "CRISPRi" to conduct a genome-wide unbiased exploration for drug targets in pancreatic cancer with DNA-damage repair deficiencies. Any top targets will be prime for translation into an early phase clinical trial for pancreatic cancer patients.

Project title: "Developing new therapeutic approaches for pancreatic cancer with homologous recombination repair defects"
Institution: University of California, San Francisco
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Alan Ashworth, PhD
Cancer Type: Pancreatic
Research Area: Drug Discovery
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
Award Program: Fellow
Sponsor(s) / Mentor(s): David Pellman, MD
Cancer Type: Pancreatic, All Cancers
Research Area: Cell Biology
Kathrin Leppek, PhD

Dr. Leppek [Layton Family Fellow] aims to combine RNA and ribosome biology with developmental biology to investigate how cells regulate protein synthesis through a process called translation. This process requires regulatory mechanisms to fine-tune when and where genes are expressed. Defective expression of certain genes gives rise to uncontrolled growth and metastasis of cancer cells. She will identify and characterize molecular components that play a functional role in mediating translational control during embryogenesis. This will be invaluable for our understanding of how deregulation of accurate gene expression underlies human diseases such as cancer.

Project title: "Mechanistic characterization of 5’UTR RNA elements that confer translational specificity to shape vertebrate embryonic development"
Institution: Stanford University
Named Award: Layton Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Maria Barna, PhD
Cancer Type: Blood, Gastric, Gynecological, Breast, Colorectal, Lung, Pancreatic
Research Area: Developmental Biology
Rushika M. Perera, PhD

Cancer cells have a unique ability to rapidly and efficiently remodel their internal composition and metabolic dependencies in order to maintain accelerated growth, metastasize and resist anti-cancer therapies. A newly identified central regulator of this increased plasticity is an internal organelle called the lysosome. Through processing and recycling of a variety of macromolecules, the lysosome serves as an important regulator of cellular remodeling and as a source of fuel for cancer cell growth.

Dr. Perera proposes to develop a novel genetically engineered mouse model that enables isolation and purification of lysosomes from three stages during the life cycle of a tumor growing within a host organism – the primary tumor, the metastatic lesion, and following tumor relapse – with a particular focus on pancreatic cancer which is highly dependent on lysosomes for growth. She will investigate how changes in lysosome function at different stages of tumor progression contribute to metabolic adaptation and survival. This work has the potential to uncover new ways to target the altered metabolism intrinsic to pancreatic cancer and other malignancies.  

Project title: "Mechanisms of cellular transformation at the single organelle level"
Institution: University of California, San Francisco
Award Program: Innovator
Cancer Type: Pancreatic
Research Area: Animal Models/Mouse Models
Chenxi Tian, PhD

Dr. Tian studies pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by an extremely stiff texture, which is caused by accumulation of excessive extracellular matrix (ECM). The compositions of ECM, known to have major effects on tumor progression, are not well understood in PDAC disease. She aims to identify global ECM changes during PDAC progression by proteomic approaches, and to investigate how these changes impact cancer progression. The uncovered ECM of PDAC will provide novel insights into diagnosis, prognosis and treatments of this very difficult disease.

Project title: "Understanding the roles of extracellular matrix proteins in pancreatic ductal adenocarcinoma progression"
Institution: Massachusetts Institute of Technology
Named Award: Sherry and Alan Leventhal Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Richard O. Hynes, PhD
Cancer Type: Pancreatic
Research Area: Invasion and Metastasis
Heather L. Yeo, MD

The cost of gastrointestinal cancer care in older adults is high, and hospital readmission after major GI cancer surgery can be particularly costly. The Center for Medicare Services (CMS) estimates that around 75% of these readmissions are preventable. For these patients, early warning signs for dehydration, infection, or other complications, if noted earlier, would allow physicians to intervene and prevent readmission. Dr. Yeo, a surgeon, has worked with programmers from Cornell Tech Campus to develop a Mobile Application (iPhone or Android compatible) for patients undergoing abdominal cancer surgery. The app tracks patients’ mobility and prompts patients to input quantitative and qualitative data regarding pain, fluid status and dietary factors in order to allow physicians to intervene earlier as needed. She is currently piloting the app for feasibility and usability, and improving the user interface so that physicians can use the app to monitor and improve patient care. The next step is a prospective randomized study to evaluate the utility of this mobile app in the prevention of readmission, thus enhancing physician-patient interactions, decreasing costs and, most importantly, improving patient care.

Project title: "Use of mobile applications to evaluate post surgical recovery in aging patients with GI cancer"
Institution: Weill Cornell Medicine
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Manish A. Shah, MD, and Deborah Estrin, PhD
Cancer Type: Gastric, Other Cancer, Colorectal, Pancreatic
Research Area: Outcomes Research
Roberto Zoncu, PhD

Cancer cell metabolism differs from that of healthy cells because cancer cells have extreme requirements for energy. An organelle inside the cell called the lysosome has recently been defined as a “metabolic signaling center,” which senses cellular nutrient levels and communicates them to a growth regulator protein called mTORC1. Dr. Zoncu proposes to synthesize novel molecules that can specifically disable the lysosomal-mTORC1 signaling pathway as a new means of starving cancer cells and thus blocking tumor growth. He will investigate how this pathway controls the function of the lysosome and another organelle, the mitochondria, in mediating the resilience of cancer cells to challenges such as starvation, hypoxia and chemotherapeutic drugs. This research may impact all cancer types, but particularly pancreatic and lung cancers, which appear to be uniquely sensitive to levels of mTORC1.

Project title: "Identifying and disabling organelle circuits that fuel cancer cell metabolism"
Institution: University of California, Berkeley
Award Program: Innovator
Cancer Type: Lung, Pancreatic
Research Area: Cell Biology
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