The Gut Microbiome in Ovarian Cancer: Identification of Microbial-derived Metabolites Involved in Antibiotic-induced Chemoresistance
Epithelial Ovarian Cancer (EOC) remains the deadliest gynecologic malignancy. Current standard of care involves neoadjuvant or adjuvant platinum based chemotherapy. Ultimately, most patients develop platinum resistance. Therapeutic options for these patients are limited, creating an unmet need to identify the mechanisms underlying platinum resistance in EOC. Our previous data indicates that ABX mediated dysbiosis leads to EOC progression and cisplatin resistance in two murine models. Restoration of the microbiome by cecal microbiome transplant reverses these effects. Thus, an intact gut microbiome harbors a tumor suppressive activity. We propose that metabolites derived from microbial metabolism are tumor suppressive in EOC. We will test this hypothesis by (1) identifying target microbial metabolites from EOC tumor bearing mice and testing their impact via in vitro and in vivo analysis on cisplatin sensitivity and tumor progression. We will also complete these analyses using data derived from human plasma samples while further expanding our previously established biorepository. The significance of these studies is twofold: identified metabolites can serve as potential markers of chemo-response in patients and lead to therapeutic advances in the future.
This project aims to identify bacterial derived molecules from our gut that alter cancer growth and drug sensitivity. Using a panel of previously identified gut microbiome derived metabolites, we will determine which metabolites harbor tumor suppressive activity in cell based and pre-clinical models of EOC. The outcome of our research has the potential to guide future treatment strategies for EOC patients including chemoprevention approaches that support gut microbial health.