Abstract The purpose of this study is to determine the optimal timing of treatment for a novel chemoprevention approach in a mouse model of Familial Adenomatous Polyposis (FAP). FAP is an autosomal dominantly inherited disorder caused by mutations in the tumor suppressor Apc (adenomatous polyposis coli) gene, which results in the formation of hundreds to thousands of polyps, predominantly in the colon and rectum. Left untreated, these polyps will form colorectal adenocarcinomas. Although surgical removal of the colon eliminates the colon cancer risk, these individuals are also at increased risk for other primary cancers, including tumors of the small intestine and stomach. Systemic chemopreventive interventions to specifically remove the pre-cancerous cells in these individuals could greatly improve their outcomes and quality of life. Recently, we have developed a new method based on the ability of combined retinoid and TRAIL (tumor necrosis factor related apoptosis inducing ligand) treatment to induce apoptosis and regression of intestinal polyps in ApcMin/+ mice, a mouse model of FAP. Treatment of these mice with retinoid causes an increase in TRAIL death receptors DR4 and DR5 as well as a concomitant decrease in the decoy receptors. APC deficiency leads to a decreased level of the anti-apoptotic protein FLIP (flice-like inhibitory protein). Thus, the combination of TRAIL and retinoid specifically targets APC deficient cells for apoptosis. Following up on these findings, we have tested the hypothesis that early stage adenomas of the intestine will respond more readily to TRAIL and retinoid treatment than those at a later stage. We used ApcMin/+ mice at either two months of age or five-six months of age. Each group of mice was given three treatments of retinyl acetate and TRAIL within one week. Following the last treatment, the intestine was harvested from each mouse and the polyps were counted. The number of polyps in each group of mice was compared with the polyp number in age matched non-treated mice. Results: When treated at two months of age, ApcMin/+ exhibit a nearly 50% decrease in polyp number following only one week of therapy. Conversely, ApcMin/+ treated at five-six months of age did not show any significant difference in polyp number compared to non-treated mice. Conclusion: Earlier stage adenomas respond more readily to the combined treatment of retinoid and TRAIL. This is likely due to additional mutations acquired by the later stage polyps. The cause of this resistance is a current area of study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1008. doi:1538-7445.AM2012-1008