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CYP17 inhibition as a hormonal strategy for prostate cancer

Nature Clinical Practice Urology volume 5, pages 610–620 (2008)Cite this article

Abstract

Androgen receptor (AR) signaling has a key role in the pathogenesis of prostate cancer. AR gene amplification, AR overexpression, and activating mutations in the AR occur more frequently as castration-resistant prostate cancer (CRPC) evolves, with intratumoral androgen levels remaining sufficient for AR activation despite castration. The source of these androgens might be either adrenal or intratumoral. AR signaling, therefore, remains a valid treatment target for patients with CRPC. CYP17 is a key enzyme for androgen biosynthesis. The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits CYP17, but remains unlicensed for this indication. Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel, selective, irreversible inhibitor of CYP17 called abiraterone, which is more than 20 times more potent than ketoconazole. Abiraterone acetate, a prodrug, has undergone phase I assessment, and is rapidly progressing from phase II to phase III trials, in view of its high level of antitumor activity. This agent is safe and well tolerated, and activity profiles suggest that approximately 50% of CRPC remains AR-ligand driven. Other CYP17 inhibitors with alternative mechanisms of action, for example VN/124-1, are in preclinical development. The rationale for and implications of CYP17 inhibition and the CYP17-targeting agents in development are discussed in this Review.

Key Points

  • Androgens and androgen receptor signaling have a key role in the pathogenesis of castration-resistant prostate cancer

  • CYP17 inhibitors might affect both adrenal and de novo castration-resistant androgen synthesis

  • CYP17 inhibitors that are more than 20-fold more potent and are more specific than ketoconazole have now been developed

  • Tumor responses seen in patients treated with the CYP17 inhibitors ketoconazole and abiraterone acetate confirm that a significant proportion of castration-resistant prostate cancers remain hormone driven

  • Abiraterone acetate, an agent that specifically and irreversibly inhibits CYP17, is well tolerated and preliminary data suggests that it has considerable antitumor activity in patients with prostate cancer

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Figure 1: The steroid biosynthesis pathway and its inhibition by prostate cancer treatments.
Figure 2: Chemical structures of pregnenolone and CYP17 inhibitors.

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Authors and Affiliations

  1. AHM Reid and G Attard are Clinical Research Fellows at the Institute of Cancer Research and the Royal Marsden Hospital, E Barrie is a Nonclinical Staff Scientist at the Institute of Cancer Research, and JS de Bono is Senior Lecturer and Honorary Consultant Medical Oncologist at the Royal Marsden Hospital and The Institute for Cancer Research, Surrey, UK.,

    Alison HM Reid, Gerhardt Attard, Elaine Barrie & Johann S de Bono

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  1. Alison HM Reid
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Correspondence to Johann S de Bono.

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Competing interests

Abiraterone acetate was discovered at the Institute of Cancer Research, which, therefore, has a commercial interest in the development of this agent. The following individuals are paid employees of the Institute of Cancer Research: Alison HM Reid, Elaine Barrie and Johann S de Bono. Dr de Bono has served as an unpaid consultant for Cougar Biotechnology, which owns the development rights for abiraterone acetate.

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Reid, A., Attard, G., Barrie, E. et al. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Rev Urol 5, 610–620 (2008). https://doi.org/10.1038/ncpuro1237

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