Investigating the Relationship between Gastrointestinal Microbiota, Androgen Receptor Axis-Targeted Therapies, and Checkpoint Inhibition in the Treatment of Advanced Prostate Cancer

Prostate cancer is one of the most common newly diagnosed cancers and leading causes of death due to cancer in American men. Studies show that some men with metastatic castrate resistant prostate cancer (mCRPC) progressing on enzalutamide respond to checkpoint inhibitors such as anti-PD-1 (pembrolizumab). It has also been shown that circulating androgens affect gastrointestinal bacteria and vice versa. Additionally, studies demonstrate that gastrointestinal bacteria have both positive and negative effects on treatment response to checkpoint inhibition. Therefore, we sought to investigate relationships between gastrointestinal bacterial composition, androgen axis targeted therapies, and response to checkpoint inhibition in mCRPC. Chapter 1 describes initial studies investigating the relationships between gastrointestinal bacterial composition, enzalutamide, and pembrolizumab in murine models. We found that conventionally housed mice often carry Akkermansia muciniphila (A. muciniphila) in their gastrointestinal tract, and that oral enzalutamide was associated with decreased fecal A. muciniphila over time. We also demonstrated that pembrolizumab is not effective as sole treatment in a murine MycCap prostate cancer model when gastrointestinal A. muciniphila is present. Oral supplementation with A. muciniphila likewise did not affect pembrolizumab efficacy. In chapter 2 we describe a novel, open-source bioinformatics microbiome pipeline for concurrently analyzing sequencing data from multiple bacterial 16S rRNA hypervariable regions. We demonstrate that hypervariable regions differ in their ability to discriminate certain taxa, and that integrating data from multiple hypervariable regions enhances the ability to accurately detect changes between groups. Chapter 3 describes the application of this bioinformatics pipeline in examining gastrointestinal compositional differences in a cohort of patients with mCRPC being treated with enzalutamide and pembrolizumab. We found that while treatment response to pembrolizumab was associated with minimal differences in alpha and beta diversity, several bacterial taxa were differentially abundant between responders and non-responders. Notably, many of these bacteria were abundant in the opposite direction of reports in other cancer types, suggesting that microbiome profiles may be unique to cancer type or previous cancer treatments. Overall, these studies lay the foundation for future work investigating the relationships between gastrointestinal microbiota and prostate cancer therapies in mCRPC