Abstract 2214: Inhibiting the mevalonate pathway with atorvastatin alters gut microbiota and has potential as an anti-cancer treatment for ovarian cancer

Abstract Statins, a mevalonate (MVA) pathway antagonist, are widely used to treat and prevent hypercholesterolemia by blocking cellular production of cholesterol. However, new research has uncovered that statins exhibit pleotropic anti-tumor and immune modulating effects, as downstream metabolites from the MVA pathway have been linked to several cellular systems commonly dysregulated in cancer patients. Furthermore, statins have been shown to induce significant changes in intestinal enterotypes in both humans and mice. This is uniquely important as studies on the intestinal microbiota have shown a strong correlation between gut health and cancer outcomes. Therefore, we hypothesized that statins could be utilized to therapeutically target pre-clinical models of ovarian cancer by modulating the systemic and tumor immune landscape as well as the intestinal microbiome. Female C57BL/6 mice injected with 5x105 ID8-BRCA1null cells received low-dose atorvastatin (5mg/kg/day, n=14) or DMSO (<2%(v/v)/day, n=14) control for 5 weeks. Histopathology was performed on necropsy tissues, and immune profiling via flow cytometry was performed on splenocytes and cells isolated from ascites to examine the impact of statins on immune cell populations. In a separate study, we administered to female C57BL/6 mice atorvastatin (5mg/kg/day, n=5) or DMSO (<2%(v/v)/day, n=5) control for 4 weeks and sequenced 16S ribosomal RNA in their stool to determine how statin affected intestinal flora. Lastly, to determine if host genetics affect statin-mediate microbial changes, we simultaneously administered atorvastatin (5mg/kg/day) or DMSO (<2%(v/v)/day) control to three commonly used inbred mice strains (C3H/He, n=3; BALB/c, n=3; C57BL/6, n=5) and compared 16S sequencing results across all three strains. Conclusion: We found that statins, in the absence of standard of care regimens, are able to elicit immune modulatory effects in an aggressive ascitic model of ovarian high-grade serous carcinoma thereby offering moderate improvements to tumor outcomes. Furthermore, we found that statins favorably alter the intestinal microbiome, increasing microbial diversity within the gut and increasing the abundance of beneficial microbiota. Importantly, our data emphasize the role of host genetics in shaping microbiome responses to statin therapy, which could have implications for patient-specific treatment strategies. Overall, these results support further research to evaluate statins' use as a therapeutic or preventive agent for ovarian cancer. Citation Format: Juliane M. Liberto, Emily Ke, Daniel Labbe, Sabrene Mechergui, Kala Visvanathan, Ie-Ming Shih, Tian-Li Wang. Inhibiting the mevalonate pathway with atorvastatin alters gut microbiota and has potential as an anti-cancer treatment for ovarian cancer [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 2214.