Optimisation of therapies targeting the gut microbiota in prostate cancer
Despite significant therapeutic advances, prostate cancer (PCa) is a leading cause of male cancer mortality, with metastatic castration-resistant prostate cancer (mCRPC) remaining fatal. PCa therapeutic development has focused on targeting cell-intrinsic mechanisms of oncogenic signaling. However, external factors such as diet and obesity also impact prostate carcinogenesis and PCa growth by altering inflammation and metabolism. Dysbiosis, or gut microbial imbalance, is implicated in carcinogenesis, anticancer drug tolerability, and efficacy. Differences in gut microbiota in patients with and without PCa have been reported.Nevertheless, we recently reported that androgen deprivation therapy in mice and prostate cancer patients selects a peculiar “unfavorable” gut microbiota capable of synthesizing androgens, contributing to endocrine resistance. We also demonstrated that gut microbiota manipulation through antibiotics, fecal microbiota transplantation, and Prevotella stercorea administration delayed the transition from hormone-sensitive prostate cancer (HSPC) to CRPC. This proposal aims to develop novel therapeutic strategies based on gut microbiota modulation for the therapy of PCa patients. We will exploit mouse models of CRPC, metabolomics, metagenomics, and proteomics approaches to address these specific objectives:I.Identify dietary or therapeutic interventions that may shift the composition of the gut microbiome towards a “favorable” signature using available pre-clinical models of PCa.II.Determine the mechanism(s) by which Prevotella stercorea contrasts the emergence of CRPC and therapeutic resistance.If successful, this proposal will be of direct therapeutic relevance for patients affected by PCa, since it will allow us to optimize novel pre- and post-biotics to prevent and/or treat PCa.