The overall objective of this Program Project Grant is to itdentify and test new ways to prevent, detect, and treat colon cancer through an increased understanding ofthe genetics, cell biology and pathogenesis of this malignancy and its precursor lesion, the adenomatous polyp. Our Program focuses on the definition of the molecular mechanisms that underlie the development ofcolon cancer following mutations in the tumor suppressor adenomatous polyposis coll (APC). Since APC is mutated in up to 85% of colorectal cancers and adenomatous polyps, improved understanding of the molecular alterations that characterize tumors harboring APC mutations could result in the identification of novel strategies for improved diagnosis and treatment of colorectal polyps and cancer. The goals of the present Program are centered on APC and other proteins that help mediate its oncogenic effects. These goals are tested in hypotheses using a variety of experimental approaches that include: 1. Utilizing high-risk, inherited APC gene mutation carriers and families in a novel interventional clinical trial that will test combined inhibition of cyclooxygenases and EGFR, two proteins that we found in the previous funding cycle to mediate the oncogenic effects of mutant APC. 2. Characterizing altered mechanisms associated with the loss of APC function, with a focus on events related to decreased retinoic acid production, excess signaling through EGFR, LEF1, TCF4 and deregulated Wnt signaling. 3. Assessing the role of KRAS as a permissive factor in colon cancer development following APC mutation. 4. Evaluating novel pathways for activation of EGFR mediated by inflammatory lipid mediators, including studies in genetically-altered mice and pre-clinical trials in murine models of colon cancer. These investigations, based on work from the previous cycle, involve carcinogenic cell functions of proliferation, differentiation, apoptosis and inflammation and, as noted, will be tested in a systems biology and translational construct utilizing cell culture, zebrafish, mouse and human models.
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