Abstract LB164: Combination of naproxen and a novel longer acting eicosapentaenoic acid analogue provide synergistic tumor protection in polyposis in rat colon (PIRC) model

Abstract

Abstract The purpose of this study was to determine whether or not Naproxen and novel TP-252 combine for synergistic tumor protection in the PIRC model. Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds of polyps that unless removed by prophylactic colectomy, will progress to CRC at an early age. In recent decades, non-steroidal anti-inflammatory drugs (NSAIDs) and ω-3 marine fish oils such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventative potential in delaying the onset of CRC in high-risk patients. In this study, we examined the tumor protective effect of Naproxen alone, or in combination with EPA in the intestinal tumorigenesis Apcam1137 PIRC rat model. Since the free fatty acid form of EPA (FFA-EPA) is readily oxidized, we included a novel longer acting chemically stabilized form of EPA (magnesium L-lysinate bis-eicosapentaenoate), TP-252. Rats were fed a modified AIN-93G diet containing 200 ppm Naproxen, alone or in combination with two dose levels of TP-252 (1.5%, or 3%) or a single concentration of FFA-EPA (2%) by weight for 20 weeks. Rats that received 200 ppm Naproxen alone showed reduced tumor number by 66% (p < 0.0001) and size by 83% (p < 0.0001), respectively, compared to rats fed AIN-93G (control diet). However, when Naproxen was combined with high-dose TP-252 (3%), tumor number and size were reduced by 95% (p < 0.0001) and 98% (p < 0.0001) respectively, when compared to control AIN-93G diet. To elucidate potential mechanisms of tumor protection, a comprehensive lipidomic analysis was performed on colon tissue and plasma to determine potential metabolic changes associated with drug treatment. Naproxen or EPA alone resulted in significantly reduced arachidonic acid (AA)-derived ω-6 eicosanoids (PGE2, LTB4, and 5-HETE), but the combination of Naproxen and EPA yielded the most significant reduction that was also correlated with tumor protection. In addition, groups receiving EPA, either as FFA or TP-252, had a dose-dependent increase in anti-inflammatory EPA-derived ω-3 eicosanoids, as well as a panel of bioactive resolvins. Our lipidomic analysis also uncovered several lipid metabolites, including PGE3, RvE2, and 5-HEPE, that were correlated with tumor protection. Further studies should be focused on dose optimization, and the role of these lipid mediators in CRC initiation and progression. (Supported by the NCI Prevent Program 75N91019D00019, Task Order 75N91019F00132). Citation Format: Ryan Beach, Daniel W. Rosenberg, Altaf Mohammed. Combination of naproxen and a novel longer acting eicosapentaenoic acid analogue provide synergistic tumor protection in polyposis in rat colon (PIRC) model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB164.