Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer
Open Access
- 14 September 2016
- journal article
- research article
- Published by Oxford University Press (OUP) in The Oncologist
- Vol. 21 (12), 1427-1435
- https://doi.org/10.1634/theoncologist.2016-0161
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.Keywords
Funding Information
- Prostate Cancer Foundation
- Patrick C. Walsh Fund
- National Institutes of Health (R01 CA185297, P30 CA006973)
- Prostate Cancer Foundation
- NIH (R01 CA185297)
- U.S. Department of Defense Prostate Cancer Research Program (W81XWH-13-2-0093, W81XWH-15-2-0050)
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