Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Area of Science:

• Oncology
• Molecular Biology
• Urology

Background:

• Prostate cancer is a leading cause of cancer death in Western countries, heavily reliant on the androgen receptor (AR) for growth.
• Current treatments like androgen deprivation therapy (ADT) are often followed by relapse, leading to castration-resistant prostate cancer (CRPC).
• Existing CRPC treatments targeting AR activity or androgen production have limitations due to AR mutations and splicing variations, leading to treatment resistance.

Purpose of the Study:

• To explore the potential of eliminating androgen receptor (AR) protein as a curative strategy for prostate cancer.
• To review emerging strategies for reducing AR protein levels and their efficacy in preclinical models.
• To highlight AR protein elimination as a viable approach to overcome AR reactivation in advanced prostate cancer.

Main Methods:

• Review of preclinical studies investigating agents that reduce AR protein levels through various mechanisms.
• Analysis of strategies including proteasome-mediated degradation, heat-shock protein inhibition, and AR splicing suppression.
• Examination of compounds targeting AR nuclear localization and AR N-terminal suppression.

Main Results:

• Several agents effectively reduce AR protein levels, leading to the elimination of xenograft tumor growth in preclinical models.
• Diverse mechanisms are employed to reduce AR protein, including enhanced protein or mRNA degradation.
• Some small chemical compounds targeting AR are progressing through clinical trials, often in combination with existing therapies.

Conclusions:

• Eliminating AR protein presents a promising therapeutic avenue for achieving a potential cure in prostate cancer.
• Strategies aimed at AR protein degradation offer a realistic solution to prevent AR reactivation during ADT.
• Further clinical investigation of AR protein-targeting agents is warranted for CRPC treatment.