Abstract 3572: Role of the gut microbiome in androgen production and prostate cancer treatment resistance

Abstract

Abstract Metastatic prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and the androgen receptor axis-targeted therapies abiraterone acetate + prednisone (AA/P) or enzalutamide. Unfortunately, most individuals undergoing these treatments develop resistance, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrate a potential link between the gut microbiota and the treatment efficacy of endocrine therapy in metastatic castration resistant prostate cancer (mCRPC). This may be due in part to gut bacterial communities with the machinery to synthesize androgens using mechanisms distinct from human cells. For example, the bacterial desAB genes (e.g., “desmolase”) that were first described in the gut commensal bacterial species Clostridium scindens convert cortisol and prednisone to the androgenic metabolites 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and ∆1-adrenosterone (∆1-AT), respectively. We hypothesize that androgen synthesis by the gut microbiota promotes treatment resistance to AA/P in advanced prostate cancer. This study aims to determine if androgen-converting gut bacterial species as well as circulating and fecal androgen levels correlate with AA/P treatment response in individuals with mCRPC using a combination of metagenomics and metabolomics. We further aim to demonstrate the relationship between gut bacterial androgen production and prostate cancer treatment response using an in vivo mouse model. Metagenomic sequencing showed an imbalance in microbial communities and identified the presence of androgen-synthesizing bacteria such as C. scindens in fecal samples of individuals undergoing treatment with AA/P. We also demonstrate that the relative abundance of C. scindens, as well as other species reported to generate androgens, are significantly enriched during metastatic disease progression on AA/P. Furthermore, targeted quantitative PCR of the bacterial desmolase (desA) gene demonstrated that absolute levels of desmolase are significantly higher in AA/P non-responders relative to AA/P responders, and trended higher in individuals with rising prostate-specific antigen (PSA) versus stable PSA while on AA/P. Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone, 11OHAD, ∆1-AT, and other androgen metabolites in association with rising PSA levels in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into 11OHAD and ∆1-AT, respectively, in vitro at 48- and 72h post-treatment, which recapitulates prior published studies. Finally, we have established a prostate cancer mouse model using a VCaP xenograft in which tumor growth was significantly inhibited by abiraterone acetate in comparison to treatment with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Overall, this study ascertains the ability of the human gut microbiota to harbor androgen-synthesizing bacteria, which in turn can be an alternative source of androgens that could impact the efficacy of the anti-androgen therapies used to treat metastatic prostate cancer. Citation Format: Angelica I. Cruz Lebron, Pedro A. Balbuena-Almodóvar, Luke Mummert, Sarah Ernst, Mark Markowski, Michelle Rudek, Jason Ridlon, Karen S. Sfanos. Role of the gut microbiome in androgen production and prostate cancer treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3572.