Abstract 6345: Establishing a preclinical cell model to assess the impact of metabolic status on the efficacy of preventive therapies: insights for the COLO-PREVENT trial

Abstract Despite numerous advances in colorectal cancer (CRC) treatment, it continues to impose a significant global burden. The COLO-PREVENT polyp prevention trial platform seeks to address this by investigating interventions in ‘elevated-risk’ cohorts identified through the NHS Bowel Cancer Screening Program (BCSP) by repurposing the drugs aspirin and metformin, as well as the dietary compound resveratrol. The seAFOod polyp prevention trial, which recruited a similar population through BCSP, reported that 82% of participants were classified as overweight or obese (BMI ≥ 25) (Hull, 2018, Lancet). This suggests that COLO-PREVENT participants may also exhibit metabolic dysregulation, potentially modulating the efficacy of preventive interventions. Obesity and type 2 diabetes, both linked to metabolic dysregulation, are well-established risk factors for CRC, supported by both preclinical and epidemiological studies. This study aims to develop an in-vitro model of metabolic dysregulation associated with high-fat diet consumption. A non-tumorigenic cell line derived from a colonic tubular adenoma (Williams, 1990, Cancer Res.) was used to explore interactions with therapies under investigation in COLO-PREVENT. Preventive activity will be assessed using MTT assays for cell viability, measurement of free fatty acid levels, analysis of reactive oxygen species (ROS), and confocal microscopy to visualize morphological changes and fatty acid droplet localization in response to treatment. Initial results indicate that clinically achievable concentrations of COLO-PREVENT therapies increase cytotoxicity when cells were cultured under normal conditions. The effect was observed after 72 h of incubation with both single agents and low-dose combinations. Among single agents, only 1 µM aspirin significantly reduced cell viability (p ≤ 0.05). Low-dose combinations further enhanced cytotoxicity, with 0.5 µM aspirin and 0.005 µM resveratrol increasing cytotoxicity to 37%, while 0.625 µM metformin with 0.0005 µM resveratrol increased cytotoxicity to 65% compared to vehicle control. When exposed to the lipids palmitic acid (PA) and oleic acid (OA) to mimic high fat intake, cells showed enhanced cytotoxicity with PA, while OA exposure had a weak proliferative effect. High concentrations of PA (1 and 5 mM) significantly reduced cell viability, causing 73% and 89% cytotoxicity, respectively, compared to control (p < 0.001). In contrast, OA exhibited weak proliferative activity across most tested concentrations. These preliminary findings suggest that metabolic dysregulation may influence the growth of colorectal adenomas and modulate the efficacy of preventive therapies. Further studies are warranted to investigate mechanisms underlying potential interactions and how this might influence precision prevention within the COLO-PREVENT framework. Citation Format: Eve Jarman, Catherine Andreadi, Karen Brown. Establishing a preclinical cell model to assess the impact of metabolic status on the efficacy of preventive therapies: insights for the COLO-PREVENT trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6345.