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

In response to nutrient changes in the environment, pancreatic cancer cells can adjust the rate of mRNA translation to selectively regulate the rate of protein production. However, the specific codons—the trinucleotide sequences that correspond to specific amino acids—and regulatory mechanisms used are not known. Dr. Banh’s research aims to decipher the laws governing how codons regulate mRNA translation in response to the nutrient environment in pancreatic cancers. As cancer cells have many codon-altering mutations and are constantly adapting to changes in the nutrient environment, these studies will offer insight into tumor evolution and may uncover novel therapeutic strategies for pancreatic and other cancer patients.

 

Project title: “Codon- and nutrient-specific regulation of mRNA translation in pancreatic cancer”
Institution: New York University Grossman School of Medicine
Award Program: Dale Frey Scientist
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 School of Medicine
Named Award: William Raveis Charitable Fund Innovator
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 W. Muir, PhD
Cancer Type: Pancreatic, All Cancers
Research Area: Chromatin 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
Cong Ma, PhD

Patients with the same cancer diagnosis may experience very distinct disease progressions and treatment responses. These differences between patients have been associated with their degree of intra-tumor heterogeneity-the genetic, epigenetic, spatial, and environmental differences between the tumor cells. Characterizing the genetic and epigenetic states of different tumor cells is key to understanding how intra-tumor heterogeneity influences tumor progression, expansion, metastasis, and treatment response. Recent advances in single-cell RNA sequencing and spatial transcriptomics (which shows the spatial distribution of RNA molecules within a tissue sample) provide new opportunities to study intra-tumor heterogeneity in higher resolution. Dr. Ma's research aims to characterize intra-tumor heterogeneity in terms of specific genetic and epigenetic measures, and eventually develop 3D tumor models that capture this heterogeneity across multiple cancer types. Dr. Ma received her BS from Zhejiang University and her PhD in computational biology from Carnegie Mellon University.

The proposed computational methods will be based on previous methods developed in the group. Dr. Ma will develop a better method for identifying tumor clones for spatially resolved transcriptomics (SRT) data using both copy number and allele information using HMM and HMRF. She will adapt optimal transport frameworks and include biological networks as prior knowledge for integrating epigenetic data with SRT and between SRT slices to construct 3D spatial tumor multi-omics models.

Project title: "Modeling spatial organization and interactions among genetic and epigenetic states across cancer types"
Institution: Princeton University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Benjamin Raphael, PhD, and Li Ding, PhD
Cancer Type: Breast, Pancreatic, All Cancers
Research Area: Quantitative Biology
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
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 can be used for 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, All Cancers
Research Area: Biochemistry
Cristina Puchades, PhD

Dr. Puchades studies ion channels – proteins embedded in the membrane surrounding a cell.  They act as molecular gates, opening in response to diverse stimuli to allow ions to flow into cells. The essential ion channel TMEM16A is required for many fundamental physiological processes, including neuronal signaling, muscle contraction, and salivary gland secretion. In cancer cells, increased activity of TMEM16A is closely linked to metastatic progression in esophageal, gastric, and pancreatic cancers. Dr. Puchades aims to understand how TMEM16A functions and how drug molecules hinder its activity. This research has the potential to guide the pharmacological targeting of TMEM16A as a novel approach for the development of anti-cancer therapeutics.

Project title: "Deciphering the molecular basis for modulation of TMEM16A activity"
Institution: University of California, San Francisco
Award Program: Fellow
Sponsor(s) / Mentor(s): Yifan Cheng, PhD, and Lily Jan, PhD
Cancer Type: Gastric, Other Cancer, Pancreatic, All Cancers
Research Area: Biophysics
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