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
Fangtao Chi, PhD

Dietary interventions such as caloric restriction (CR) and ketogenic diet (KD) are reported to limit tumor growth partially by modulating stem cell function. The intestine functions as the main organ of nutrient absorption and, due to rapid tissue renewal via intestinal stem cells (ISCs), is sensitive to shifts in the body’s metabolic state before and after eating. Both CR and KD conditions dramatically enhance the activity of an enzyme in ISCs known as HMGCS2. This enzyme controls ketogenesis, the conversion of fatty acids into ketone bodies as a means of producing energy when glucose is unavailable. Dr. Chi aims to dissect the role of ketone body metabolites in modulating intestinal stem cell function and tumor growth. With a better understanding of how intestinal stem cells adapt to diverse diets, he hopes to identify new strategies or dietary interventions that prevent and reduce the growth of cancers in the intestinal tract. Dr. Chi received his PhD from the University of California, Los Angeles and his BS from Zhejiang University.

Project title: "Understanding how ketone body metabolites influence intestinal stemness, immune responses and tumorigenesis"
Institution: Massachusetts Institute of Technology
Award Program: Fellow
Sponsor(s) / Mentor(s): Ömer H. Yilmaz, MD, PhD
Cancer Type: Colorectal
Research Area: Stem Cell Biology
Tin Yi Chu, PhD

Cancer cells form complex interactions with the various normal cells in their environment, including immune cells, fibroblasts, and blood vessels. These interactions are essential for cancer cells to grow, evade immune surveillance, and become metastatic or resistant to certain therapies.  Spatial transcriptomics refers to a method of visualizing the distribution of RNA molecules in a tissue sample, allowing us to assign specific cell types to their locations. Dr. Chu aims to develop a statistical framework to infer how different cell types interact with each other based on spatial transcriptomics data. He will use this statistical framework to study cell-cell interactions in both colorectal cancer and inflammatory bowel disease, a risk factor for colorectal cancer.

Dr. Chu will develop a hierarchical Bayesian statistical model to deconvolve the spatial transcriptomic data and then resolve cell type-specific information. Based on the deconvolved spatial data, he will then deploy a Bayesian spatial model to infer the interaction between various cell types.

Project title: "Statistical modeling of cell-cell interactions in normal intestine, inflammatory bowel disease and colorectal cancer using single cell and spatial transcriptomics"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Dana Pe’er, PhD, and Elaine V. Fuchs, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Quantitative Biology
Lauren E. Cote, PhD

Dr. Cote is exploring embryonic development to better understand how cells cooperate and build complex tissues. Since cancer cells often erroneously redeploy developmental programs and behaviors, her research into how neighboring cells align will yield insights into how cancerous cells metastasize and invade other tissues. Dr. Cote is combining tissue-specific genetic manipulations and laser cell ablations with live imaging during Caenorhabditis elegans digestive tract development to reveal how intracellular organization in one cell type can influence the alignment, polarity, and function of cells in the neighboring tissues.

Project title: "Constructing one continuous digestive tract, cell by cell"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jessica L. Feldman, PhD
Cancer Type: Gastric, Other Cancer, Breast, Colorectal, All Cancers
Research Area: Developmental Biology
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: University of Pittsburgh
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Jeremy N. Rich, MD, and Lin Zhang, 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
Piro Lito, MD, PhD

Therapies that directly target cancer-promoting oncoproteins have revolutionized the treatment of cancer. Cancers, however, are primed to adapt and evolve in the presence of treatment, resulting in an ability to resume growth despite the presence of therapy. Utilizing cutting-edge new techniques that allow the determination of genetic alterations in single cancer cells, Piro aims to understand the principles that govern the evolution of resistance during therapy and identify novel therapeutic interventions that halt this process. His specific focus will be on improving the efficacy of KRAS inhibition for treatment of lung and colorectal cancers.

Project title: "Modeling responses to targeted ERK signaling inhibition at the single-cell level"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Neal X. Rosen, MD, PhD, and Charles M. Rudin, MD, PhD
Cancer Type: Colorectal, Lung
Research Area: Experimental Therapeutics
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