A road map to comprehensive androgen receptor axis targeting for castration-resistant prostate cancer

Area of Science:

• Oncology
• Endocrinology
• Cancer Biology

Background:

• Gonadal androgen suppression is insufficient for prostate cancer treatment due to adrenal and intratumoral androgen sources.
• Residual androgens enable prostate cancer adaptation into castration-resistant prostate cancer (CRPC).
• The androgen receptor (AR) axis remains critical in CRPC, with inhibitors like abiraterone and enzalutamide showing efficacy.

Purpose of the Study:

• To explore a novel therapeutic strategy for prostate cancer by comprehensively targeting the AR axis.
• To investigate the potential benefits of simultaneous, multi-level, and multi-site AR axis inhibition at the initiation of endocrine therapy.

Main Methods:

• The study discusses the limitations of current androgen suppression therapies.
• It proposes a paradigm shift towards simultaneous combination therapy targeting androgen synthesis, metabolism, and action.
• The approach considers gonadal, adrenal, and intratumoral sources of androgens.

Main Results:

• Current therapies achieve suboptimal ablation of intratumoral androgens and AR axis signaling.
• This suboptimal suppression allows cancer cells to survive and evolve into CRPC.
• The study highlights the need for more effective AR axis targeting.

Conclusions:

• Comprehensive AR axis targeting at multiple levels and sites simultaneously offers a transformative therapeutic opportunity.
• Maximal first-line AR axis suppression via combination therapy warrants clinical investigation.
• This approach may induce maximal cancer cell apoptosis and improve patient outcomes before resistance develops.