Pancreatic Cancer

Current Projects
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
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. 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 [Robert Black Fellow] 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 [CRIS Cancer Foundation Breakthrough Scientist] 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 / 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
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
Sharanya Sivanand, PhD

Dr. Sivanand aims to study how metabolic alterations impact pancreatic ductal adenocarcinoma metastases. Pancreatic tumors primarily metastasize to the liver and the lung. It is known that genetics, tissue of origin, and tumor microenvironments can impose metabolic demands on cancer cells. However, it is unclear whether primary tumors and associated metastases during disease progression are metabolically different. Her research will provide insight into metabolic demands of tumors originating in the pancreas and identify metabolic liabilities that may restrict metastatic growth to certain tissue types.

Project title: "Understanding metabolic heterogeneity in primary and metastatic tumors"
Institution: Massachusetts Institute of Technology
Award Program: Fellow
Sponsor(s) / Mentor(s): Matthew G. Vander Heiden, MD, PhD
Cancer Type: Pancreatic
Research Area: Cell Biology
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