Engineered repressors are potent inhibitors of androgen receptor activity
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Greg N. Brooke1,2, Sue M. Powell1, Derek N. Lavery1, Jonathan Waxman1, Laki Buluwela1, Simak Ali1 and Charlotte L. Bevan1
1 Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, W12 0NN, UK.
2 School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK.
Charlotte Bevan, Email: [email protected]
Keywords: androgen receptor, prostate cancer, anti-androgen, castrate resistant prostate cancer
Received: September 05, 2013 Accepted: November 20, 2013 Published: January 21, 2014
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
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