SAT-312 Role of the gut microbiome in androgen production and prostate cancer treatment resistance

Abstract Disclosure: A. Cruz Lebron: None. P.A. Balbuena-Almodóvar: None. L. Mummert: None. S.E. Ernst: None. M. Markowski: None. M. Rudek: None. J. Ridlon: None. K.S. Sfanos: None. Background: Advanced prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and androgen receptor axis-targeted therapy. Unfortunately, most individuals undergoing these therapies develop resistance to treatment, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrated a potential link between the gut microbiota and treatment efficacy 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. Therefore, we hypothesized that androgen synthesis by the gut microbiota promotes prostate cancer growth and negatively impacts prostate cancer treatment, leading to non-responsiveness. Aims & Methods: This study aims to i) identify bacterial species responsible for gut androgen biosynthesis, ii) determine if circulating and fecal androgen levels in individuals with mCRPC correlate with treatment response using metagenomics and metabolomic studies, and iii) determine the relationship between gut androgen production and prostate cancer treatment response using in vivo mouse models. Results: Metagenomic sequencing showed an imbalance in microbial communities at the phylum level and identified the presence of androgen-synthesizing bacteria such as Clostridium scindens in fecal samples of individuals undergoing treatment with abiraterone acetate/prednisone (AA/P). Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone and Δ1-Androstenedione (Δ1-AT) in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into the androgen precursor 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and Δ1-AT in vitro at 48- and 72h post-treatment. Lastly, 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 than those treated with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Conclusions: 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 prostate cancer treatment responsiveness. Presentation: Saturday, July 12, 2025