Prevention of APC-Dependent Intestinal Carcinogenesis

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DESCRIPTION (provided by applicant): Mutations/deletions in the adenomatous polyposis coli (APC) gene occur in the majority of sporadic colon cancers. One mechanism by which APC mutations promote tumorigenesis is to increase transcription of ornithine decarboxylase (ODC), via a c-MYC dependent process, and polyamine synthesis. Polyamine metabolism in the intestinal and colonic mucosa is also affected by polyamine catabolism, a process regulated by the peroxisomal proliferator activated receptor 3 (PPAR3). This protein affects polyamines pools by inducing the transcription of the spermidine/spermine N1- acetyltransferase (SSAT), which encodes an enzyme initiating polyamine catabolism and export. The hypothesis to be tested in this proposal is that the APC and PPAR3 roles in intestinal and colon carcinogenesis are mediated by tissue-specific mechanisms involving polyamine metabolic genes. A corollary to this hypothesis is that targeting selected steps in polyamine metabolism will be effective means of colon cancer prevention in individuals with high risk of colon cancer. Three specific aims will test this hypothesis. First, we will use genetic methods to conditionally knockout the Apc-dependent gene c-Myc, and the c-Myc target gene Odc, in intestinal and colonic epithelial tissues in mouse models in order to determine the roles of these genes in chemical carcinogen-induced colon carcinogenesis. Second, we will determine the roles of Ppar3 and the Ppar3 target gene Ssat in intestinal and colonic tumorigenesis in mouse models. We will use genetic methods for conditional, tissue-specific knockout of Ppar3 in intestinal and colonic epithelia, in order to evaluate the role of this gene in colon carcinogenesis in azoxymethane-treated mouse models. Finally, we will evaluate novel agents that influence features of polyamine metabolism alone and in combination, as possible innovative strategies for colon cancer chemoprevention. Isogenic cell culture and mouse models will be used. The long-term goal of these studies is to develop effective chemoprevention strategies for colon, and potentially other epithelial, cancers. Tissue polyamine contents are influenced by specific synthetic, catabolic, uptake and efflux mechanisms. We have found that oncogenes and tumor suppressor genes relevant to colon carcinogenesis influence some of these processes. We will systematically evaluate agents that activate or suppress intestinal and colonic polyamine pools by mechanisms affecting polyamine uptake and metabolism, in addition to ODC inhibition, for their potential as novel colon cancer chemopreventive agents. We hope to identify interventions that can be used in combination with current strategies for which efficacy data exists (e.g., NSAIDS), or which are under current investigation in clinical cancer chemoprevention trials (e.g. DFMO). The studies proposed will investigate specific biochemical pathways involved in colon carcinogenesis, using genetically modified human cell and mouse models. The long-term goal of this work is to develop safe and effective strategies for the prevention of colon cancer in people at risk for this disease.