Abstract 7299: Preventing CRC progression in FAP rat model using a combinational targeting of TRAIL signaling and inflammation

Abstract

Abstract Colorectal Cancer (CRC) is among the leading causes of mortality globally, with high incidence rates in developed countries including the US. While FAP patients are prone to develop CRC in their lifetime, recent rising trends among young adults is also a major concern. Hence, preventing CRC 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, orally active small molecule ONC201, alone and in combination with the NSAID naproxen (NAP) for CRC prevention in the PIRC rat model representing FAP cohort. Male PIRC rats were bred inhouse and randomized by age into placebo and intervention groups (N=15). Starting at 6 weeks of age, experimental groups were administered either ONC201 alone by gavage [25mg/kg; 2X/week or 50mg/kg; 1X/week]; NAP in AIN-76A diet [200 ppm; continuously or 1 week ON/OFF]; or a combination of both agents, while placebo group received vehicle only. After 26 weeks of treatment, rats were euthanized and intestines were evaluated for tumor incidence and multiplicity. H&E stained colonic tumor sections were histologically classified as hyperplastic polyps, adenomas (AD), and adenocarcinomas (ADCA). Gross tumor data indicated significant reduction in colonic polyps in both the NAP alone and NAP+ONC201 groups without any overt-toxicites. Histological analyses also demonstrated strong suppression of AD progression to ADCA as well as a significant decrease in the number of ADs and ADCAs (p<0.05) in the treatment groups compared to the placebo. ONC201 regimens modestly reduced AD (19%-27% less, p<0.05) but showed strong inhibition of ADCA (45%-59% less, p<0.0001). A significant reduction of AD and ADCA was seen in NAP continuous (54% & 87% less respectively; p<0.0001) and intermittent (34% & 68% less respectively; p<0.0001) dosing regimens. As anticipated, the NAP continuous treatment had better efficacy than the intermittent dosing regimen. Notably, the combination treatment showed >90% (p<0.0001) inhibition of ADCA and 40%-57% (p<0.0001) inhibition of ADs. Importantly, ONC201+ NAP treatment also resulted in an additional 45% - 70% reduction of ADCA (p<0.0001) when compared to the NAP alone treatment. Thus, our data showed that the combination groups with NAP intermittent dosing demonstrated ~90% inhibition of ADCA, suggesting the synergistic effect of the two agents in preventing CRC progression. Molecular analysis of the rat tumors and additional analyses in in-vitro tumoroid models suggested induction of TRAIL (TRAIL, DR5, FADD), increased apoptosis (Caspases), and a decrease in proliferation markers (PCNA, Cyclin D1) and pro-inflammatory cytokines (IL1b, IL13 etc.). Our data suggests NAP/ONC201 combo has no toxicities, warranting further investigation of CRC interception in high-risk FAP patients (Funding by NCI-PREVENT 75N91019D00020-75N91020F00004). Citation Format: Venkateshwar Madka, Gopal Pathuri, Karthikkumar Venkatachalam, Surya P. Singh, Anil Singh, Nicole Stratton, Stanley Lightfoot, Shizuko Sei, Mark S. Miller, Chinthalapally V. Rao. Preventing CRC progression in FAP rat model using a combinational targeting of TRAIL signaling and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7299.