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

Abstract

Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

Androgen receptor mutations for precision medicine in prostate cancer

“…Interestingly, mutant AR can promiscuously be activated by adrenal androgens, nonandrogenic steroids, and even antiandrogens (Waltering et al 2012). In addition, clinical data between AR mutations and the efficacy of ARPIs have recently been accumulating (Huang et al 2022). Thus, the clinical importance of AR mutations has been suggested, and information about the mutation status could contribute to the selection of effective treatment for individual patients.…”

Prognostic factors in Japanese men with high-Gleason metastatic castration-resistant prostate cancer

“…Patients with metastatic CRPC prefer androgen receptor signaling inhibitors (ARSIs) to docetaxel because of their severe side effects and worse quality of life (2,3).…”

Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical

“…However, for men diagnosed with distal metastasis, the survival rate is only 30%. Currently, localized prostate cancer is treated mainly with surgical removal of the gland or radiation therapy, which has been shown to be feasible [ 210 ]. However, for patients at high risk of distal metastasis, hormonal deprivation caused by surgical removal of the gland which leads to castration of resistant prostate cancer (CRPC) is a major clinical challenge [ 211 ].…”