ARE ARE Prostate cancer cell Prostate cancer cell A Castration-resistant prostate cancer growth B agents targeting castration-resistant prostate cancer Testis Adrenal gland GnRH Androgen (A) Androgen (A) Adrenal gland Testis CYP17 inhibitors Prostate cancer cell Abiraterone TAK-700 TOK-001 GnRH agonists / antagonists or castration AR AR Antagonist MDV-3100 ARN-509 EZN-4176 AR antisense AR AR AR Antagonist Androgen (A) Androgen (A) EPR-001 AR modulator AR AR nuclear transport inhibitor hsp-27 AR Prostate cancer cell ODM-201 Androgen (A) AR A hsp-27 degradation AR AR hsp antisense ARE ARE OGX-427 AR AR hsp-27 ARE AR A Androgen (A) ARE Growth arrest AR Fig.1. (A) Prostate cancer cell growth in the presence of castration can be maintained through intra- tumoral or adrenal production of androgen (light blue box), by overexpression of wt-AR (rectanglular blue box) or mutated/alternatively-spliced AR (oval blue box). Hsp-27 (red box) prevents degradation of cytoplasmatic unbound AR. Androgen-bound AR or mutated/spliced AR transports to the nucleus, binds to androgen responsive elements on the DNA, leading to AR-induced gene tanscription and cellular growth. (B) Agents targeting CRPC include CYP17 inhibitors, AR antagonists, AR modulators, AR antisense molecules, AR nuclear transport inhibitors and heat-shock-protein antisense molecules (grey boxes). The generic names of the compounds currently evaluated in clinical trialsa re depicted in red. ARE AR-induced gene transcription tumorigenesis