AR Gene Rearrangements and AR Signaling in Prostate Cancer

PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is the most frequently diagnosed male cancer. Surgery or radiation therapy are curative treatments for localized PC while systemic endocrine therapies are standard-of-care for advanced or metastatic PC. The molecular target of endocrine therapy is the androgen receptor (AR), a transcription factor activated by the steroid hormones testosterone and dihydrotestosterone. Because PC cells require AR for proliferation and survival, inhibiting testosterone production (with gonadotropin releasing hormone analogs and/or abiraterone acetate) and using competitive AR antagonists to block testosterone actions (such as enzalutamide, apalutamide, and darolutamide) are the cornerstones of endocrine therapy. Unfortunately, endocrine therapy is not curative and the disease will inevitably progress to advanced castration-resistant PC (CRPC). CRPC is a lethal disease stage for which no curative therapies exist. Our analysis of tumor specimens from patients has shown that one of the most frequent alterations occurring in CRPC is structural rearrangement of the AR gene. Our preliminary data show that AR gene rearrangements uncouple the AR transcription factor from endocrine regulation and also from negative feedback regulation that occurs when tumor suppressor genes like PTEN are lost. This uncoupling renders AR activity insensitive to endocrine therapies and promotes CRPC. The long term goals of this project are to harness AR gene rearrangements as biomarkers to guide more effective use of current and future CRPC therapeutics, and to develop novel therapeutics that can overcome the effects of AR gene rearrangements. To achieve these goals, we will develop new mouse models of CRPC progression that harbor AR gene rearrangements and PTEN loss, and use these models to identify mechanisms by which AR gene rearrangements promote PC progression and therapeutic resistance. These models will fill a long-standing void in the field: a lack of mouse models reflecting clinically-relevant AR alterations. We will test the utility of these models for advancing CRPC research by evaluating CRPC responses to AR-targeted therapeutics in a whole-organism context. We will also use third- generation genome structural variation analysis techniques to interrogate the structure of certain AR gene rearrangements that occur via complex, multi-step mechanisms. This work is expected to provide clarity about the role and origin of the most frequent and complex patterns of AR gene rearrangements in CRPC. Finally, therapeutic vulnerabilities of CRPC models harboring AR gene rearrangements will be evaluated using a set of candidate AR-targeted therapeutics. We will also use computational methods to nominate non-AR-targeted therapeutics that will have efficacy in CRPC tumors harboring AR gene rearrangements. Collectively, this work is expected to enhance understanding of AR gene rearrangements in CRPC progression, and yield new models, biomarkers, and therapeutics that can be used to combat this lethal subset of the disease.