Familial adenomatous polyposis (FAP) and Lynch syndrome (LS) are hereditary colorectal cancer (CRC) syndromes that are definable high-risk populations for clinical prevention studies. FAP is a colon polyposis and CRC predisposition syndrome caused by germ-line APC mutations. Frequent colonoscopy and prophylactic colectomy are standard of care. While several clinical and animal studies have demonstrated chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for FAP, there are no FDA-approved drugs for this indication. LS is the most common hereditary CRC syndrome, affecting >1 million Americans. LS is caused by mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2 or in EPCAM, resulting in deficient DNA MMR and confers 70-80% lifetime risk of developing CRC. Thus, FAP and LS are well defined patient populations with up to 90% lifetime CRC risk that are highly likely to benefit from effective CRC chemoprevention. Omega (ω)-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), suppress intestinal polyp formation. A diet containing the free fatty acid form of EPA (EPA-FFA) reduced polyp burden in ApcMin/+ mice. Importantly, treatment of FAP patients for 6 months with EPA-FFA showed 22% and 30% net reduction in colon polyp number and size, in a randomized, double-blinded, placebo-controlled trial. The underlying mechanism of the tumor-suppressive activity of EPA is its ability to act as a competitive inhibitor of arachidonic acid (AA) oxygenation. EPA-FFA significantly increases intestinal mucosal EPA content effectively displacing AA from membrane phospholipids. Both AA and EPA serve as substrates for the cyclooxygenases (COXs) and lipoxygenases (LOXs) that collaborate in the formation of a complex array of bioactive lipid metabolites. Several metabolic products formed from AA, including PGE2, are strongly associated with CRC promotion. However, minor structural differences between AA and EPA alter synthesis of many lipid metabolites, which contributes to the tumor-suppressive properties of the ω-3 PUFAs. However, high-purity EPA-FFA rapidly oxidizes. A novel ionic derivative of EPA, magnesium l-lysinate biseicosapentaenoate (TP-252), which is chemically more stable and more effective at inhibiting PGE2 and other tumor-promoting metabolites, is specifically designed to deliver therapeutic levels of EPA-FFA to the intestinal mucosa. Recently TP-252 was evaluated for its efficacy in ApcΔ14/+ mice. NSAID naproxen inhibits COXs and has shown benefit against CRC in preclinical models. In clinical studies for rheumatoid arthritis, osteoarthritis, and juvenile arthritis, Naproxen has similar efficacy but fewer side effects than aspirin or indomethacin. Naproxen is the most effective NSAID to increase survival of LS/HNPCC mice. Using an intestine and colorectum targeted Msh2 deletion LS mouse model, Fishel et al. tested different NSAIDs on LS model survival. Treatment with dietary naproxen (331 ppm) almost doubled LS mice survival compared to 400 ppm aspirin treatment. These preclinical data led to the initiation of NCI-DCP Clinical Consortium study Phase Ib Biomarker Trial of Naproxen in Lynch Syndrome Mutation Carrier (NCT02052908). The overall goal of the project is to evaluate whether TP-252 alone or in combination with naproxen will reduce CRC tumor burden in two rodent genetic models; a highly penetrant APC-mutant rat, Pirc, that models FAP, and an innovative novel VcMsh2 mouse that models LS.