Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling. Several of these approaches are currently in clinical practice, while some are still pending further development and clinical evaluation. This remarkable progress has resulted from extensive laboratory, pre-clinical and clinical efforts, and mechanistic learnings from the therapeutic success and failures. In this review, we describe the importance of androgen signaling in prostate cancer biology and advances made over the years to effectively target this signaling pathway. We also discuss emerging data on the resistance pathways associated with the failure of various androgen signaling- targeted therapies and potential of this knowledge for translation into future therapies for prostate cancer.