Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer. (14th September 2016)

• Record Type: Journal Article
• Authors: Antonarakis, Emmanuel S.; Chandhasin, Chandtip; Osbourne, Erica; Luo, Jun; Sadar, Marianne D.; Perabo, Frank
• Is Part Of: Oncologist. Volume 21:Number 12(2016)
• Page Start: 1427
• Page End: 1435
• Publication Date: 2016-09-14
• Subjects: EPI-506 -- Androgen receptor -- N-terminal domain -- Prostate cancer; Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2016-0161
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. Abstract : This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of androgen receptor (AR)-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity and, as a result, may affect a broader AR population, including mutational and splice variant ARs.