Differential Wnt Dependencies in Colon Epithelium.

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Project Summary/Abstract This proposal details a five-year training plan for the development of a research program focused on elucidating the therapeutic potential of superimposed additional Wnt signaling on colonic neoplasia. The molecular driver shared across the vast majority of colonic neoplasms is constitutive Wnt signaling, most commonly caused by loss of function mutations in the APC gene. The loss of function of APC permits beta catenin to constitutively translocate to the nucleus and induce the formation of colonic adenomas which can further mutate into colon cancer. To date, strategies to inhibit Wnt signaling for therapeutic purposes have failed. However, other elements of the beta catenin destruction complex that work with APC, such as GSK3 alpha and beta can be pharmacologically inhibited. Therefore, instead of inhibiting Wnt signaling, and informed by the concept that a “just right” amount of Wnt signaling may be selected for in tumor cells, we hypothesized additional Wnt signaling would be deleterious to tumor cells but would simultaneously enhance the function of normal cells. This project will elucidate fundamental dependencies of Wnt signaling in normal tissues as well as tumors. Ultimately, I believe this will engender a specific therapy for adenomas, to which there is no existing medical therapy other than polypectomy, and additionally provide a broadly applicable and potentially safe approach to treat colorectal cancer. I am clinically trained pathologist and physician scientist seeking K08 support for mentored research. This work will be mentored by Prof. Omer Yilmaz and Prof. Robert Langer. Prof. Yilmaz is a pathologist and physician-scientist, and studies the effects of diet on intestinal stem cells and state- of-the-art intestinal organoid models. Prof. Langer has fundamentally transformed and defined biomedical engineering, is the most cited engineer in history, and most recently his expertise in nanoparticle delivery provided the foundation for the Moderna COVID-19 vaccine. The work will be conducted at the Massachusetts Institute of Technology and Massachusetts General Hospital, both world class institutions of the highest caliber. I have assembled a scientific advisory committee consisting of world class cancer biologists to help guide my scientific progress, consisting of Prof. Tyler Jacks, Prof. Michael Yaffe, and Prof. William Kaelin. This K08 mentored research award will ensure I have the time and resources to develop expertise in cancer biology and explore this promising therapeutic and biologically intriguing concept of increased Wnt signaling to specifically treat colonic neoplasia. This topic will provide ample substrate for me to grow as an independent physician scientist.