Genetic events leading to APC-dependent colon cancer in high-risk families:COX

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In Project 1 we will test the hypothesis in a novel interventional clinical trial that concurrent inhibition of cyclo-oxygenases and EGFR will induce duodenal and colorectal adenomatous polyp regression in a cohort of high-risk, familial adenomatous polyposis (FAP) and attenuated FAP subjects. The two protein classes inhibited in this trial were found in the previous funding cycle to mediate the oncogenic effects of mutant adenomatous polyposis coli (APC) gene. Examining adenoma regression and specific markers of these two pathways in a clinical trial will not only address specific clinical needs, but will also provide the human model for defining how these pathways are perturbed in carcinogenesis following loss of APC function. These same pathways will be addressed in the other projects of this Program in cell culture, zebrafish and mouse models, thereby forming a unified approach to determining downstream effects of APC function loss. The knowledge gained will serve to identify novel strategies for diagnosis, prevention and treatment of adenomatous polyps and colon cancer. FAP and attenuated FAP subjects will be studied both because of the multiple polyp phenotype, and because these conditions arise from inherited APC gene mutations, the same gene somatically mutated in the large majority of colon adenomas and cancers. Safe and effective chemoprevention for colon polyps and cancer would be of substantial benefit for both sporadic and high risk forms of colorectal neoplasia. Duodenal polyps and cancer are a particular problem for FAP and attenuated FAP patients, as present treatments are far from satisfactory. We will specifically enroll 100 FAP and attenuated FAP subjects in a double blind, placebo controlled trial to examine the combinatorial effect of sulindac (a general COX inhibitor) and erlotinib (an EGFR inhibitor) to induce regression of duodenal and colorectal adenomatous polyps. We will draw from a combined cohort of approximately 300 local FAP and attenuated FAP subjects in our high-risk familial colon cancer registry. Secondary endpoints that complement the studies of other projects of this Program include: the change in aberrant crypt foci before and after treatment; and, changes in expression of WNT, EGFR and KRAS cellular signaling pathways in both adenomatous polyp and normal tissue biopsy samples. Finally, appropriate samples obtained in this project will be utilized by Projects 2-4.