Pancreatic Cancer

Current Projects
Daniel J. Delitto, MD, PhD

Pancreatic cancer develops in the midst of intense scarring and fibrous connective tissue (fibrosis). The architects of this scarring are cells called fibroblasts, known to fuel cancer growth and promote treatment resistance. Dr. Delitto's research is focused on the interface between cancer-induced fibrosis and the immune system. He has shown that fibroblasts play a significant role in shielding cancer cells from immune cells. By altering how fibroblasts sense tissue damage, Dr. Delitto has uncovered a mechanism that reactivates the immune system to fight the tumor. He aims to further develop these findings into a novel immunotherapy regimen for pancreatic cancer.

Project title: "Pathogen sensing in fibroblasts restrains antitumor immunity in pancreatic cancer"
Institution: Stanford University
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Michael T. Longaker, MD, DSc
Cancer Type: Pancreatic
Research Area: Immunotherapy
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 [William Raveis Charitable Fund Innovator] 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. She plans to 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
Award Program: Innovator
Cancer Type: Breast, Lung, Pancreatic
Research Area: Cancer Genetics
Isabella Fraschilla, PhD

Pancreatic cancer remains unresponsive to current chemotherapy and immunotherapy treatments. However, with the recent development of mRNA vaccines and drugs that target cancer cell mutations, there is hope for a new generation of immune-based therapies. The ability of adaptive immune cells, called cytotoxic T cells, to kill cancer cells is central to anti-tumor immunity. Using mouse models of human pancreatic cancer, Dr. Fraschilla [Merck Fellow] plans to identify the flags presented by cancer cells that enable T cells to recognize them as foreign and kill them. One category of flags that label cancer cells as foreign may be proteins from bacteria that prefer to replicate within the tumor environment. This investigation of cancer cell targets will inform the development of future vaccines to treat cancer and prevent tumor regrowth or metastases. Dr. Fraschilla received her PhD from Harvard University, Cambridge and her BS from Emory University, Atlanta.

Project title: "Examining bacteria as a source of tumor antigens"
Institution: Massachusetts Institute of Technology
Named Award: Merck Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Tyler E. Jacks, PhD
Cancer Type: Pancreatic
Research Area: Tumor Immunology
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 / Washington University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Benjamin Raphael, PhD (Princeton University), and Li Ding, PhD (Washington University)
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
Ahmed Roman, PhD

Dr. Roman aims to develop mathematical tools to determine which genes are associated with resistance to chemotherapy. Given genomic information from pancreatic cancer patients whose tumors are resistant or sensitive to chemotherapy, this tool will identify genes that distinguish the two populations. These genes can then be explored as potential drug targets that can sensitize chemotherapy-resistant tumors to treatment.

Dr. Roman’s research relies on the use of information theory to improve the ability of neural networks to find genes whose RNA expression distinguishes chemotherapy-sensitive from resistant patients. Another research direction is to leverage prior knowledge, accumulated over decades about gene-gene interactions in the laboratory, to inform the architecture of the neural networks or use large foundation models training on millions of cells to study cancer.

Project title: "Signal bottleneck theory for dissecting gene interactions in pancreatic cancer"
Institution: Dana-Farber Cancer Institute
Named Award: Leslie Cohen Seidman Quantitative Biology Fellow
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Eliezer M. Van Allen, MD, and Andrew J. Aguirre, MD, PhD
Cancer Type: Pancreatic
Research Area: Genomics
Yapeng Su, PhD

One in 64 people in the U.S. develops pancreatic cancer in their lifetime and only 9% will survive 5 years. This rate has barely changed in the last 40 years; better innovative treatments are urgently needed. Among the most promising immunotherapies is adoptive T cell therapy (ACT), which involves infusion of the patients' own immune T cells that have been engineered outside of their body to make them selectively kill cancer cells. ACT has been effective against certain blood cancers but has had limited success against solid tumors, including pancreatic cancers. Dr. Su will quantitatively assess the mechanisms that contribute to the decreased effectiveness of ACT against pancreatic cancer. He will use specimens obtained from mouse models and pancreatic cancer patients receiving ACT to develop computational frameworks that can be applied to single-cell sequencing data and other large datasets. His findings should inform the design of next-generation ACT against pancreatic cancer and potentially other solid tumors. Dr. Su received his BS from Tianjin University and his PhD in engineering/systems biology from the California Institute of Technology.

Dr. Su will develop and apply thermodynamic-inspired information-theoretical approaches to deconvolute the high-dimensional single-cell multi-modal data to resolve master-regulators contributing to adoptive cell therapy (ACT) ineffectiveness in the context of pancreatic cancer. In addition, he will utilize Bayesian statistical methods on the spatial multiomic data to reconstruct the cellular- and molecular factors that compromise the efficacy of ACT for pancreatic cancer in mice and humans.

Project title: "Quantitative analysis to elucidate spatial-temporal heterogeneity of therapeutic T cell dysfunction mechanisms in the context of adoptive cell therapy against pancreatic cancer"
Institution: Fred Hutchinson Cancer Research Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Philip D. Greenberg, MD, and Raphael Gottardo, PhD
Cancer Type: Pancreatic
Research Area: Immunotherapy
Erik Van Dis, PhD

The innate immune system is the body's first line of defense against pathogens. The innate immune sensor MDA5 detects nucleic acids derived from pathogenic genomes or damaged cells and drives the production of cytokines, an important signaling molecule in the immune inflammatory response. MDA5 can be aberrantly activated by host nucleic acids, however, leading to autoimmune activation. Hyperactive MDA5 alleles are associated with the development of autoimmune diabetes. Dr. Van Dis [Robert Black Fellow] aims to define the innate immune signaling pathways that initiate autoimmune diabetes to better understand immune activation pathways in the pancreas and guide the development of novel immunotherapies for pancreatic cancer. Dr. Van Dis received his PhD from the University of California, Berkeley and his BA from Carleton College, Northfield.


Project title: "Investigating innate immune activation in the autoimmune pancreas"
Institution: University of Washington
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Daniel B. Stetson, PhD
Cancer Type: Pancreatic
Research Area: Basic Immunology
Lexy von Diezmann, PhD

Dr. von Diezmann is a biophysicist who studies how cells regulate the pathway used to repair broken DNA. Errors in specific DNA repair pathways are an early step in the development of many cancers, such as with defects in homologous recombination for breast, ovarian, and pancreatic cancers. The Diezmann lab uses high-resolution microscopy techniques to visualize the process by which DNA breaks are designated for specific repair fates, working primarily in live meiotic nuclei of the model organism C. elegans. By elucidating the mechanisms by which protein assemblies form and transmit information along chromosomes and throughout the nucleus, her lab will help provide a foundation for the development of novel chemotherapies based on modulating the DNA damage response.

Project title: "Single-molecule dynamics of DNA repair assemblies in live cells"
Institution: University of Minnesota
Award Program: Dale Frey Scientist
Cancer Type: Pancreatic, All Cancers
Research Area: Chromosome and Telomere Biology
Qinheng Zheng, PhD

Dr. Zheng [Connie and Bob Lurie Fellow] is developing small molecules that selectively inhibit the protein K-Ras(G12D). Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer due to the infrequency of early diagnosis and the lack of targeted or immune therapies. A high percentage (>90%) of PDAC patients harbor KRAS mutations, with the majority expressing the K-Ras(G12D) missense mutation. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting oncogenic K-Ras(G12D). K-Ras lacks an apparent surface topology for reversible small molecule binding, leading to its notorious characterization as “undruggable.” Dr. Zheng is searching for small molecules that form a permanent bond with the mutant protein at its missense site and inhibit its interaction with effector proteins.

Project title: "Drugging K-Ras(G12D) with targeted covalent inhibitors"
Institution: University of California, San Francisco
Named Award: Connie and Bob Lurie Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Kevan M. Shokat, PhD
Cancer Type: Colorectal, Lung, Pancreatic
Research Area: Chemical Biology
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