Abstract B090: Gut microbial suppression of epithelial ovarian cancer and attenuation of chemoresistance: opportunity for probiotics in patient care to improve survival

Abstract

Abstract Up to 80% of ovarian cancer patient tumors will recur, become platinum resistant, and require additional treatment. Platinum resistance is correlated with poor overall survival and reduced therapeutic options for epithelial ovarian cancer (EOC) patients, a leading cause of gynecologic cancer death. Our findings identify a microbial tumor suppressive activity that is disrupted by antibiotics including vancomycin, metronidazole, neomycin, and ampicillin. Starting with a retrospective clinical analysis of OC patients, we found antibiotic use during chemotherapy treatment is associated with poor overall survival. In pre-clinical studies, we found that broad spectrum antibiotics (ABX) therapy, including metronidazole, ampicillin, vancomycin, and neomycin, augments tumor growth of EOC and leads to resistance to cisplatin. In follow up studies we determined vancomycin and metronidazole are sufficient to accelerate ovarian cancer growth and response to cisplatin therapy. Mechanistically, we determined that tumors from ABX treated mice exhibited increased proliferation, reduced apoptosis, decreased DNA damage in cisplatin treated specimens, and increased angiogenesis compared to control treated mice. As these are functional indicators of increased cancer stem cells (CSCs), we analyzed the tumors by RNAseq and single cell spheroid analysis for stem cell frequency. Tumors from ABX treated immune competent mice contained a higher frequency of cisplatin-induced CSCs than tumors from control treated mice. Tumors from untreated mice did not show increased CSCs. We determined that ABX treatment unmasked a microbiome dependent immune suppressor of cancer stem cells as tumors from immune deficient mice exhibited cisplatin induced CSCs in presence or absence of ABX. Finally, we determined that repletion of the microbiome via cecal transplants derived from ABX or control treated mice to recolonize the microbiome of ABX treated mice is sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut-derived tumor suppressor. We identified microbial metabolites suppressed in ovarian cancer patients and reduced by ABX in mice as candidate compounds that underlie the tumor suppressive activity. Collectively, the findings indicate the gut microbiome delivers a tumor suppressive signal that is unmasked by ABX treatment. We propose a probiotic strategy as a complement to standard of care may yield improved outcomes in ovarian cancer treatment. Citation Format: Ofer Reizes, Laura Chambers, Chad M. Michener, Mark Brown, Justin D. Lathia, Mohammed Dwidar, Naseer Sangwan, Roberto Vargas, Zeneng Wang, Adeline Hajjar. Gut microbial suppression of epithelial ovarian cancer and attenuation of chemoresistance: opportunity for probiotics in patient care to improve survival [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B090.