Human diseases are often driven by abnormal gene regulation.  This involves DNA binding transcription factors (TFs) that begin misinterpreting the genetic information.  The Androgen Receptor (AR) is one such TF responsive to testosterone in male-specific organs, and the AR goes rogue in the context of prostate cancer.  The Gryder lab has discovered new mechanisms by which the AR rewires the genome and the 3D epigenome in prostate cancer.  We have developed a new chemical probe that causes the AR to shutdown 3D loops between enhancers (long-range regulatory DNA elements) and target genes. Furthermore, we are exploring the role of liquid-liquid phase separation as a mechanism for the formation of 3D clusters in the prostate cancer epigenome, providing new clues as to how molecular assembly at key genetic locations is occurring, and how drugs may act upon these clusters for therapeutic benefit. 

 

Technical Abstract:  

Androgen Receptor (AR) amplification during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Antagonists of the AR fail to benefit these mCRPC patients who have dramatic increases in AR expression. Inverse agonists functionally switch hormone receptors from activators to repressors of their target genes, but inverse agonists of the AR have not yet been identified. We designed the first AR inverse agonists (ARIA). Mechanistically, these inverse agonists bind the ligand-binding domain of the AR, cause AR nuclear localization, elicit recruitment of co-repressors to AR response elements, and reconfigure chromatin by reducing histone acetylation. ARIA treatment causes the collapse of loops between enhancers and promoters at key genes in the AR-driven epigenome. Transcription of AR target genes, such as KLK3 (encoding Prostate Specific Antigen, PSA), is potently and selectively reduced. The ARIA BG-15a and the pharmacokinetically optimized BG-15n are orally available and reduce tumor growth in antagonist-resistant in vitro and in vivo models of mCRPC. ARIA therapeutics represents a promising new strategy for treating patients with relapsed AR-driven mCRPC tumors.