Despite significant advances in early diagnosis, therapeutic drug development, and preventive efforts, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality in the United States. Thus, new prevention strategies are urgently needed, especially for individuals with precancerous lesions or genetic predispositions, such those with familial adenomatous polyposis (FAP). ONC201 is a selective antagonist of dopamine receptor D2 that reduces cell proliferation and induces TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis via integrated stress response activation and AKT/ERK inactivation. It is highly specific for cancer cells, having no effect on normal cells at concentrations that inhibit cancer cell growth. ONC201 is orally available and has demonstrated a favorable safety profile in rats and dogs, as well as in Phase 1 trials in advanced solid tumors. In the Phase 1 trials, ONC201 was administered at doses up to 625 mg once weekly for 3 weeks. No drug-related toxicities greater than grade 1 were reported, and there were no treatment discontinuations or dose modifications due to drug-related toxicity. Some evidence of efficacy (stable disease) was also observed. ONC201 is currently being tested in several Phase 2 trials (e.g. NCT03034200, NCT03099499, NCT03295396, NCT03485729, NCT02525692, and NCT02420795). In terms of CRC, ONC201 has been shown to reduce the viability of HCT116 cells in vitro (6) and to inhibit the growth of HCT116 xenografts in vivo (5). In a recently completed PREVENT Task Order (https://projectreporter.nih.gov/project_info_description.cfm?aid=9360353&icde=50111042), ONC201, administered by gavage 2X/week at doses of 25 and 50 mg/kg, significantly reduced the incidence and multiplicity of colonic tumors, as well as the multiplicity of small intestinal tumors, in both male and female azoxymethane (AOM)-treated APCmin/+ mice without inducing any signs of toxicity. Non-steroidal anti-inflammatory drugs (NSAIDs) have also shown promise as CRC chemopreventive agents, although their long-term use is hindered by concerns for gastric and cardiac toxicity. For example, 200 and 400 ppm naproxen, administered in the diet, reduces the multiplicity of adenomas, non-invasive adenocarcinomas, and invasive carcinomas when administered to AOM-treated rats continuously or on an intermittent schedule (1 week on and 1 week off). Furthermore, sulindac synergistically induces apoptosis in a variety of colon cancer and adenoma cell lines and in FAP-derived ex-vivo adenoma segments when combined with recombinant human TRAIL. The purpose of this Task Order is to expand upon the above-mentioned studies by (a) investigating the chemopreventive activity of ONC201 in the polyposis in the rat colon (Pirc) model, which, in contrast to tne APCmin/+ mouse model, primarily develops colonic tumors and thus more closely recapitulates human FAP, and (b) testing the hypothesis that the combination of ONC201 with naproxen will lead to enhanced efficacy while reducing the toxicity of the NSAID.