Colorectal and Gastric Cancers

Current Projects
Caitlin A. Brennan, PhD

Dr. Brennan [Dennis and Marsha Dammerman Fellow] studies colorectal cancer and its connection to the human microbiota--the collection of bacteria and other microbes found associated with the body in both healthy and disease states. One such organism is Fusobacterium nucleatum, a bacterium that is naturally found in the mouths and gastrointestinal tract of healthy individuals. This bacterium is also observed in high abundance in some colorectal tumors relative to healthy colon tissue within the same person; experimental studies have demonstrated that this bacterium actively promotes tumor development. Her research will investigate how Fusobacterium signals to both the immune system and other microbes in the developing tumor environment, offering insight into the potential utility of Fusobacterium as a diagnostic or therapeutic target for colorectal cancer.

Project title: "Mechanisms underlying Fusobacterium nucleatum-driven colorectal cancer"
Institution: Harvard T.H. Chan School of Public Health
Named Award: Dennis and Marsha Dammerman Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Wendy S. Garrett, MD, PhD
Cancer Type: Colorectal
Research Area: Microbiology
Arnold S. Han, MD, PhD

Cancer immunotherapy utilizes the body’s own sophisticated defenses to kill cancer cells. Recently, strategies that mobilize the immune system to target cancer have shown great promise in the clinic. Despite its enormous promise, however, immunotherapy is only effective in a relatively limited subset of cancers in a limited group of patients. The continued success and advance of cancer immunotherapy will require novel and innovative approaches. T cells are the cells within the immune system that mediate most anti-tumor immune responses. Dr. Han is studying tumor T cells using unique tools to improve our fundamental understanding of tumor immunity and also to directly test a new therapeutic strategy, which is based upon his hypothesis that our bodies produce T cells that are capable of specifically targeting a patient’s own tumors. His proposed research investigates a strategy to identify these T cells and enable them to realize their full potential through genetic engineering. His work investigates T cell immunity in human colorectal cancer, a highly prevalent cancer in which immunotherapy has had very limited success. He anticipates his findings will be applicable in 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
June-Yong Lee, PhD

Dr. Lee [HHMI Fellow] studies how the cells and molecules of the immune system within the tumor microenvironment contribute to initiation, tumor progression, and responses to anti-cancer therapy. Of the immune components, cells called interleukin-17-secreting lymphocytes have pivotal pathogenic roles in multiple cancers. He aims to elucidate the regulatory mechanisms by which this pathogenicity is controlled. Ultimately, a better understanding of the pathways may suggest promising targets for therapeutic strategies aimed at reducing the risk of cancer.

Project title: "Investigation of potential roles of serum amyloid A in peripheral Th17 cell pathogenicity"
Institution: New York University School of Medicine
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Dan R. Littman, MD, PhD
Cancer Type: Colorectal
Research Area: Tumor Immunology
Kathrin Leppek, PhD

Dr. Leppek [Layton Family Fellow] aims to combine RNA and ribosome biology with developmental biology to investigate how cells regulate protein synthesis through a process called translation. This process requires regulatory mechanisms to fine-tune when and where genes are expressed. Defective expression of certain genes gives rise to uncontrolled growth and metastasis of cancer cells. She will identify and characterize molecular components that play a functional role in mediating translational control during embryogenesis. This will be invaluable for our understanding of how deregulation of accurate gene expression underlies human diseases such as cancer.

Project title: "Mechanistic characterization of 5’UTR RNA elements that confer translational specificity to shape vertebrate embryonic development"
Institution: Stanford University
Named Award: Layton Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Maria Barna, PhD
Cancer Type: Blood, Gastric, Gynecological, Breast, Colorectal, Lung, Pancreatic
Research Area: Developmental Biology
Jose M. Ordovas-Montanes, PhD

Dr. Ordovas-Montanes studies how inflammation in the gut influences individual epithelial and immune cells. Inflammation is one of the largest risk factors for developing colon cancer. A better understanding of the cellular factors involved in precipitating malignancy may lead to novel approaches for blocking the initiation of cancer and restoring the gut to a healthy balanced state.

Project title: "Single-cell genomic approaches for tracing the contribution of inflammation to human colon cancer"
Institution: Massachusetts Institute of Technology
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Alex Shalek, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Basic 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
Philip A. Romero, PhD

Dr. Romero is a biomedical engineer whose expertise is in the area of microfluidics. He proposes to develop new technology that can be used to detect circulating tumor cells (CTCs) in the bloodstream. CTCs are cells that have detached from a solid primary tumor and entered into the bloodstream; they can go on to colonize distant sites and form metastases. Detecting CTCs is an enormous challenge, as the cells are present at an ultra-low abundance (1 out of billions of blood cells). His approach is to develop a highly specific system, a “DNA-based logic circuit,” to detect and profile CTCs, which could ultimately be applied for cancer diagnosis, prognosis indication, and measurement of a patient’s response to treatment.

Project title: "Digital circulating tumor cell detection using scalable molecular logic"
Institution: University of Wisconsin, Madison
Award Program: Innovator
Cancer Type: Breast, Colorectal, Lung, Prostate, Sarcoma
Research Area: Biomedical Engineering
Esen Sefik, PhD

Dr. Sefik is examining the connection between obesity, cancer and the microbiome. An estimated 600 million people worldwide suffer from obesity, with 15-20% of deaths from cancer in the US alone linked to obesity. Recent studies in mice highlight the importance of intestinal bacteria and immune cells in obesity and colorectal cancer; however, these roles are not yet well characterized in humans. She will   analyze how high fat diet and obesity-associated intestinal bacteria change intestinal immunity in mice that harbor the human immune system and the human microbiota. This will help resolve some of the existing discrepancies and discover new players that are relevant to obesity and cancer in humans and help engineer better-targeted, combined therapies to colorectal cancer, especially in cases where existing immunotherapy fails.

Project title: "The effect of microbes, diet on the intestinal immune system in the context of obesity and cancer"
Institution: Yale University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Richard A. Flavell, PhD
Cancer Type: Colorectal, All Cancers
Research Area: Basic Immunology
Harshabad Singh, MBBS

Cancers involving the lower esophagus (esophageal adenocarcinomas) have dramatically increased in number over the last several decades. The reason for rise in this cancer is not completely understood. However, long before these esophageal cancers arise the normal esophageal multilayered squamous lining (or epithelium) is replaced by a single layered columnar epithelium which has features similar to the lining of the intestine and is known as Barrett’s esophagus. Dr. Singh proposes to investigate the origins and factors governing the genesis of Barrett's esophagus and understand its specific vulnerability to progress to cancer. This work will yield insights into disease mechanisms and reveal novel preventive strategies for esophageal adenocarcinomas.

Project title: "Cellular origins of Barrett’s esophagus and its role in development of adenocarcinoma"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Ramesh A. Shivdasani, MD, PhD
Cancer Type: Gastric, Other Cancer
Research Area: Epigenetics
Peter J. Turnbaugh, PhD

[Nadia’s Gift Foundation Innovator]

Variations in drug efficacy and toxicity between patients are a major limitation to the long-term treatment of cancer. Even if the initial treatment is successful, cancers can return due to the emergence of cancer drug resistance. Dr. Turnbaugh seeks to determine how the gut microbiome (bacteria residing in the human body) contributes to drug efficacy and resistance. He will combine microbiology and pharmacology approaches to identify new microbiome-based biomarkers for monitoring and predicting acquired drug resistance. The findings will also have broad implications for development of more effective treatment regimens for patients with colorectal as well as other cancers

Project title: "The gut microbiome: an unexpected contributor to cancer drug resistance"
Institution: University of California, San Francisco
Named Award: Nadia’s Gift Foundation Innovator
Award Program: Innovator
Cancer Type: Colorectal
Research Area: Microbiology
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