Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Abstract

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer [1–5]. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) abundance and activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

“…Aggregating cancer clusters 1-8 and performing differential expression and pathway analysis of this aggregated cancer cluster against benign luminal cell clusters revealed that the Hallmark MYC Targets V1 gene set was the top upregulated pathway and androgen response the top downregulated pathway in the cancer clusters (Figure 2G, and Table S4). The universal upregulation of MYC targets and downregulation of the androgen response pathway across all cancer clusters are consistent with recent reports characterizing the antagonistic relationship between MYC and androgen response genes [51][52][53] . Including the Dang MYC Targets Up gene set in GSEA 54 reaffirmed significant upregulation of MYC targets across all cancer clusters (Figures 2F-G).…”

Efficacy and safety of bipolar androgen therapy in castration-resistant prostate cancer following abiraterone or enzalutamide resistance: A systematic review

“…Clinical investigations have shown that BAT is effective ( 12 – 14 ). Thus, BAT is safer and more effective than cytotoxic drugs ( 15 ). BAT can restore some patients’ sensitivity to drugs, such as Abi and Enz, showing significant advantages in treating CRPC patients ( 16 ).…”