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Colorectal Cancer (CRC) is the third most common cancer and leading cause of mortality in the US. While the rate of CRC incidence has steadily dropped in the last decades, recent rising trends among young adults are a major concern. Hence, preventing CRC in the general population would aid in reducing cancer mortality, especially in high-risk FAP patients for which there are no FDA approved preventive agents. Here, we evaluated TRAIL-inducing agent ONC201, alone and in combination with NSAID naproxen (NAP) for CRC prevention in PIRC rat model of FAP. PIRC rats (20 female rats/group) are bred and randomized by age into control and intervention groups. Starting at 6 weeks of age, PIRC rats were treated with ONC201 by gavage [25mg/kg; 2X/week (LD) or 50mg/kg; 1X/week (HD)]; NAP 200 ppm in AIN-76A diet [continuously or 1 week ON/OFF]; or the combination of ONC201 and NAP. Control group rats received vehicle only. Colonic polyps’ (CP) development (occurrence, number, and size) was monitored by periodic colonoscopies and upon termination at 32 weeks of age. Colonoscopy data indicated significantly fewer CPs in the HD ONC201, NAP alone dosing regimens, and combination groups. At termination, colonic tumors were harvested and subjected to histopathological evaluation. Colonic tumors were histologically classified as hyperplastic polyps, adenomas, and adenocarcinomas (ADCA). In vehicle treated rats, histological assessment showed multiplicity of 2.4±0.4 (Mean±SEM) hyperplastic polyps; 9.14±0.92 adenomas, and 2.4±0.27 ADCA. A significant decrease in the number of hyperplastic polyps (p90% inhibition of adenomas. Importantly, LD ONC201 inhibited colonic ADAC multiplicity by 78.8% (p Citation Format: Venkateshwar Madka, Gopal Pathuri, Karthikkumar Venkatachalam, Srikanth Chiliveru, Yuting Zhang, Nandini Kumar, Nicole Stratton, Stanley Lightfoot, Mark S. Miller, Shizuko Sei, Chinthalapally V. Rao. Colon cancer preventive efficacy of ONC201 and naproxen alone or in combination in FAP relevant PIRC rat model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB114. |
