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.

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.

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.

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.

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.

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.

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.

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.  

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.