Colorectal and Gastric Cancers

Current Projects
Todd A. Aguilera, MD, PhD

There is a critical need for new therapeutic approaches to treat advanced stage rectal cancer, which has increased incidence in younger people and poor prognosis. Working with a multidisciplinary team, Dr. Aguilera is leading a randomized clinical trial that combines an anti-CD40 agonist immunotherapy with radiation and chemotherapy for locally advanced rectal cancer. The drug aims to activate the protein CD40 on dendritic cells which plays a critical role in generating T-cell immunity. As part of the study, Dr. Aguilera is investigating the factors that influence a patient's immune response to this combination treatment with the goal of optimizing therapy for difficult gastrointestinal cancers. If the proposed treatment is successful, it could become a new therapeutic standard that lowers the risk of metastasis, improves survival, shortens the treatment course and potentially avoids the need for surgery.

Project title: "Immunologic responses to short course radiotherapy in rectal adenocarcinoma and the impact of CD40 agonist immunotherapy"
Institution: University of Texas Southwestern Medical Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Robert D. Timmerman, MD, and Yang-Xin Fu, MD, PhD
Cancer Type: Colorectal
Research Area: Tumor Immunology
Edmond M. Chan, MD

Defects in the cellular DNA repair machinery can promote cancer formation and cause cancer cells to rely on back-up DNA repair processes. These cancer cells are particularly vulnerable to drugs called PARP inhibitors, which target a DNA repair process known as homologous recombination. Dr. Chan hypothesizes that a similar treatment strategy can be used for cancers with deficiencies in DNA mismatch repair, which causes microsatellite—short, repeated sequences of DNA—instability (MSI). Microsatellite instability is found most often in certain colon, stomach, uterine and ovarian cancers. Using CRISPR screening technology, Dr. Chan discovered that cancer cells with faulty mismatch repair become dependent on a gene called WRN to survive. He is characterizing this vulnerability for MSI cancers with the goal of finding new drugs that inhibit this pathway.

Project title: "Validating a novel synthetic lethal target for microsatellite unstable cancers"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Adam J. Bass, MD
Cancer Type: Gastric, Gynecological, Colorectal
Research Area: Cancer Genetics
Gregory P. Donaldson, PhD

Dr. Donaldson is investigating the difference between a healthy mucosal surface and a tumor-promoting surface in the gut. Bacteria in the gut associate intimately with the surface of the intestine, where they exert a constant influence on the immune system throughout an organism’s life. Studies indicate that certain gut bacteria in cancer patients reside in the mucus of the intestinal surface and may promote (or potentially inhibit) the growth of tumors, perhaps through effects on the immune system. Uncovering specific “molecular conversations” that maintain a healthy community of mucosal bacteria may lead to novel therapies to prevent the origin of colorectal cancers in addition to treating existing tumors.

Project title: "Cross-talk between B lymphocytes and bacteria in the maintenance of a non-inflammatory mucosal microbiome"
Institution: The Rockefeller University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Daniel Mucida, PhD
Cancer Type: Colorectal
Research Area: Basic Immunology
Karuna Ganesh, MD, PhD

Over 90% of cancer deaths are caused by metastasis, the spread of cancer cells to distant organs, where uncontrolled cancer cell growth lethally compromises organ function. Despite recent advances, current treatments fail to effectively control metastasis. Dr. Ganesh is growing colorectal cancer cells, removed from patients during surgery, as three-dimensional “organoids.” This cutting-edge technology models the complexity of human organs more accurately than cells growing in a dish. Using colorectal cancer organoids, her group is studying how cancer cells gain the ability to spread and grow outside their organ of origin. Her work is uncovering core signaling modules required for metastasis, with the goal of developing more effective treatments for patients with advanced cancers. Dr. Ganesh works under the mentorship of Joan Massague, PhD, at Memorial Sloan Kettering Cancer Center, New York.

Project title: "Leveraging patient-derived organoid models to define the molecular determinants of metastatic regeneration"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Joan Massagué, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Invasion and Metastasis
Arnold S. Han, MD, PhD

Cancer immunotherapy mobilizes the body's own sophisticated defenses to target and kill cancer cells. Despite its enormous promise, immunotherapy is only effective in a subset of cancers in a small group of patients. Dr. Han is investigating the role of the immune system's T cells in human colorectal cancer, which has limited treatment success with immunotherapy. He is using unique tools to improve our fundamental understanding of tumor immunity and to directly test a new therapeutic approach based on his hypothesis that our bodies produce T cells capable of specifically targeting a patient's tumors. His proposed research explores a strategy to identify these T cells and use genetic engineering to enable them to realize their full potential. He anticipates his findings will be applicable to other types of cancers as well.

Project title: "Precision T cell receptor-based cancer therapies"
Institution: Columbia University
Award Program: Innovator
Cancer Type: Colorectal
Research Area: Tumor Immunology
Dennis J. Hsu, MD

DNA stores the information for making all the proteins in an organism. Transfer RNA (tRNA) plays a key role in building the proteins from this blueprint. tRNA molecules recognize specific sequences (three-letter codons) and deliver the corresponding amino acids needed to make a protein. Dr. Hsu recently found that certain starvation conditions can cause some tRNAs to be modulated in colorectal cancer cells. He will study the changes in tRNA levels that occur in response to cellular starvation states. He aims to shed light on how cancer cells adapt to starvation, which potentially can lead to new therapeutic approaches to target metabolic dependencies in cancer.

Project title: "Metabolic determinants of codon usage bias in colorectal cancer"
Institution: Memorial Sloan Kettering Cancer Center/The Rockefeller University
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Sohail F. Tavazoie, MD, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Cancer Genetics
Christina L. Hueschen, PhD

Dr. Hueschen studies the motility of Apicomplexan parasites, which cause malaria, foodborne illness (toxoplasmosis) and infections in immunocompromised cancer patients. These parasites move through the human body using a mechanism called "gliding" to migrate over host cells and through the surrounding extracellular matrix. Dr. Hueschen's goal is to understand how molecules inside the parasite are organized, coordinated and regulated to produce forces that direct movement. This research has the potential to aid in the development of therapies to prevent opportunistic infections.

Project title: "Molecular basis and regulation of apicomplexan parasite motility"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Alex Dunn, PhD
Cancer Type: Gastric, Brain, Colorectal, All Cancers
Research Area: Cell Biology
Ryan Moy, MD, PhD

Dr. Moy is focusing on key genes and pathways that control metastasis of colorectal cancer to the liver. Dr. Moy’s research could potentially lead to new treatment strategies that can block or delay metastatic progression of colorectal cancer and other gastrointestinal malignancies. Understanding this process at the molecular level has the potential to impact patient survival.

Project title: "Identifying the key drivers and mechanisms underlying metastatic liver colonization in colorectal cancer"
Institution: Memorial Sloan Kettering Cancer Center/The Rockefeller University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Sohail Tavazoie, MD, PhD
Cancer Type: Colorectal
Research Area: Invasion and Metastasis
Abigail E. Overacre-Delgoffe, PhD

Dr. Overacre-Delgoffe is utilizing unique tools to address how the interaction between the host’s immune system and gut microbes affects colon tumor progression and patient responsiveness to current immunotherapies. Currently, colon cancer patients show an extremely limited response to immune-based therapies and have very poor survival rates. The colon is a unique environment that is composed of host cells and numerous bacteria and microbes that have evolved with the host. Dr. Overacre-Delgoffe aims to understand the basic mechanisms of immunotherapy resistance due to microbiome-immune system interactions, which may aid in developing more effective therapeutics for colon cancer.

Project title: "Microbiome control of the tumor microenvironment: harnessing immunosuppression and exhaustion"
Institution: University of Pittsburgh
Award Program: Fellow
Sponsor(s) / Mentor(s): Timothy W. Hand, PhD, and Olivera J. Finn, PhD
Cancer Type: Colorectal
Research Area: Tumor Immunology
Deepshika Ramanan, PhD

Dr. Ramanan [National Mah Jongg League Fellow] studies the interplay between commensal microbes and immune cells in the intestine, and how these interactions influence the progression of inflammation and colorectal cancer. Her research particularly focuses on a cell type that dampens inflammatory responses, known as regulatory T cells. In the intestine, these cells can be broadly categorized into two subsets that differ in origin and responsiveness to microbes, but their exact functions remain unclear. She aims to identify the specific functions of these different subsets in intestinal inflammation, tissue repair, and tumor pathogenesis. These studies could provide invaluable information that can be harnessed to improve current cancer immunotherapy options.  

Project title: "Identifying functions of regulatory T cell subsets in intestinal inflammation and colorectal cancer"
Institution: Harvard Medical School
Named Award: National Mah Jongg League Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Christophe Benoist, MD, PhD
Cancer Type: Colorectal
Research Area: Tumor Immunology
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