Details

Autor(en) / Beteiligte

• CLEGG, Nicola J
• WONGVIPAT, John
• APARICIO, Anna
• DOROW, Steven
• ARORA, Vivek
• GANG SHAO
• JING QIAN
• HONG ZHAO
• GUANGBIN YANG
• CHUNYAN CAO
• SENSINTAFFAR, John
• WASIELEWSKA, Teresa
• JOSEPH, James D
• HERBERT, Mark R
• BONNEFOUS, Celine
• DARIMONT, Beatrice
• SCHER, Howard I
• SMITH-JONES, Peter
• KLANG, Mark
• SMITH, Nicholas D
• DE STANCHINA, Elisa
• NIAN WU
• OUERFELLI, Ouathek
• TRAN, Chris
• RIX, Peter J
• HEYMAN, Richard A
• JUNG, Michael E
• SAWYERS, Charles L
• HAGER, Jeffrey H
• OUK, Samedy
• DILHAS, Anna
• YU CHEN
• GRILLOT, Kate
• BISCHOFF, Eric D
• LING CAI

Titel

ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment

Ist Teil von

• Cancer research (Chicago, Ill.), 2012-03, Vol.72 (6), p.1494-1503

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.