Abstract LB114: Colon cancer preventive efficacy of ONC201 and naproxen alone or in combination in FAP relevant PIRC rat model
Authors: Madka Venkateshwar , Pathuri Gopal , Venkatachalam Karthikkumar , Chiliveru Srikanth , Zhang Yuting , Kumar Nandini , Stratton Nicole , Lightfoot Stanley , Miller Mark S. , Sei Shizuko , Rao Chinthalapally V. 
Published: April 2023

Abstract
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 (p&lt;0.05) was observed in rats treated with combination of ONC201 and NAP continuous dosing regimens. LD and HD ONC201 regimens resulted in modest (11.3%, p=0.45) and significant (48.8%, p&lt;0.0001) inhibition of colonic adenoma multiplicity, respectively. As anticipated, NAP dosing regimens showed 78-85% inhibition (p&lt;0.0001) of adenoma multiplicity. Combination treatment showed &gt;90% inhibition of adenomas. Importantly, LD ONC201 inhibited colonic ADAC multiplicity by 78.8% (p&lt;0.0001) and remaining treatment groups showed no colonic ADACs. This histological data clearly showed that ONC201 (25 mg 2X/week or 50 mg 1x/week) significantly suppresses colonic tumor progression to colon adenoma and adenocarcinomas. NAP, either continuously or intermittent dosing, resulted in 85% and 78% inhibition of adenoma multiplicities, respectively, suggesting that intermittent dosing may be similarly effective for CRC prevention. Biomarker analysis suggested increased apoptosis (TRAIL, Caspase-3) and decrease in proliferation markers (PCNA, Cyclin D1). Our data warrants investigating ONC201 with NAP combination for CRC prevention in high risk FAP patients. (Supported by NCI-PREVENT 75N91019D00020-75N91020F00004)
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.