Targeting Aberrant AR-FL and AR-V Expression and Activity to Overcome Therapy Resistance in Metastatic Castration-Resistant Prostate Cancer

The androgen receptor (AR) is a transcription factor that is activated by androgens and turns on expression of the growth and survival genes that drive prostate cancer. Therapies have been developed that target the activation of AR by androgens. However tumors commonly acquire therapeutic resistance by increasing the production of AR or androgens, by acquiring mutations in AR, or by producing alternate forms of AR (AR-variants) that do not rely on androgens to become activated. New strategies are needed to target AR in order to prevent therapeutic resistance and disease progression. Dr. Huang and team are studying a novel therapeutic paradigm in which the expression, DNA binding activity, and transcriptional activation of AR are simultaneously targeted to avoid treatment resistance and the development of castrate resistant prostate cancer (CRPC). The enhancer mRNA sequence of the PSA gene (PSA eRNA) is regulated by AR and controls the expression of a number of other AR-regulated genes by modulating the AR transcriptional complex. Whether expression of the PSA eRNA is associated with resistance to abiraterone acetate will be examined in metastatic tumor biopsies from CRPC patients enrolled in a clinical trial. The effect of targeting the PSA eRNA as a therapeutic strategy will be tested in CRPC preclinical laboratory models. Finally, the effect of co-targeting the expression, DNA binding activity, and transcriptional activation of AR will be tested in enzalutamide-resistant prostate cancer models. Small molecules that target the ability of AR to bind to DNA will be combined with molecules that target the PSA eRNA to block induction of genes by AR. In a second strategy, molecules that target both AR and AR-variants will be combined with deleting a major transcriptional control region of the PSA eRNA. What this means for patients: Resistance to androgen receptor (AR) targeting therapies are common and can result in drug resistance and progression to lethal castration resistant prostate cancer (CRPC). Dr. Huang and team are studying a new mechanism of targeting AR activity and determining whether combining this strategy with agents that target other aspects of AR activity will result in a more effective therapy. If successful, this project will result in a new, more potent therapy for the treatment of medically-resistant prostate cancer.