TY - JOUR
T1 - Targeting the N-terminal domain of the androgen receptor
T2 - A new approach for the treatment of advanced prostate cancer
AU - Antonarakis, Emmanuel S.
AU - Chandhasin, Chandtip
AU - Osbourne, Erica
AU - Luo, Jun
AU - Sadar, Marianne D.
AU - Perabo, Frank
N1 - Funding Information:
Emmanuel S. Antonarakis has received funding from the Prostate Cancer Foundation and the Patrick C. Walsh Fund and National Institutes of Health Grants R01 CA185297 and P30 CA006973. Jun Luo is currently funded by a Prostate Cancer Foundation grant, NIH Grant R01 CA185297, and U.S. Department of Defense Prostate Cancer Research Program Grants W81XWH-13-2-0093 and W81XWH-15-2-0050.
Publisher Copyright:
© AlphaMed Press 2016.
PY - 2016/12
Y1 - 2016/12
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - EPI-506
KW - N-terminal domain
KW - Prostate cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85006746979&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2016-0161
DO - 10.1634/theoncologist.2016-0161
M3 - Article
C2 - 27628492
AN - SCOPUS:85006746979
VL - 21
SP - 1427
EP - 1435
JO - Oncologist
JF - Oncologist
SN - 1083-7159
IS - 12
ER -