Richards, J., Lim, A. C., Hay, C. W., Taylor, A. E., Wingate, A., Nowakowska, K., Pezaro, C., Carreira, S., Goodall, J., Arlt, W., McEwan, I. J., de Bono, J. S., Attard, G. (2012) Interactions of Abiraterone, Eplerenone, and Prednisolone with Wild-type and Mutant Androgen Receptor: A Rationale for Increasing Abiraterone Exposure or Combining with MDV3100. CANCER RESEARCH, 72 (9). pp. 2176-2182. ISSN 0008-5472

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Abstract

Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an antiandrogen. Abiraterone, a rationally designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires coadministration with glucocorticoids to curtail side effects. Here, we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess, can also bind to and activate signaling through wild-type or mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. In fact, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide, or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism. Cancer Res; 72(9); 2176-82. (C) 2012 AACR.

Item Type:	Article
Authors (ICR Faculty only):	De-Bono, Johann
All Authors:	Richards, J., Lim, A. C., Hay, C. W., Taylor, A. E., Wingate, A., Nowakowska, K., Pezaro, C., Carreira, S., Goodall, J., Arlt, W., McEwan, I. J., de Bono, J. S., Attard, G.
Additional Information:	ISI Document Delivery No.: 986MI Times Cited: 0 Cited Reference Count: 20 Richards, Juliet Lim, Ai Chiin Hay, Colin W. Taylor, Angela E. Wingate, Anna Nowakowska, Karolina Pezaro, Carmel Carreira, Suzanne Goodall, Jane Arlt, Wiebke McEwan, Iain J. de Bono, Johann S. Attard, Gerhardt Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology); Amgen; Astellas; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Dendreon; Enzon; Exelixis; Genentech; GlaxoSmithKline; Medivation; Merck; Novartis; Pfizer; Roche; Sanofi-Aventis; Supergen; Takeda; Janssen-Cilag; Veridex; Millennium Pharmaceuticals; Ipsen; Cancer Research UK; Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK; Department of Health[C51/A7401]; NIHR clinical lectureship; Welcome Trust; Prostate Cancer Foundation, Santa Monica, CA; Prostate Action, London, UK; Medical Research Council (MRC) UK[G0801473]; Chief Scientist's Office, Scottish Government; NHS Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. J.S. de Bono has received consulting fees from Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, and Takeda, and grant support from AstraZeneca. G. Attard has received consulting fees from Janssen-Cilag, Veridex and Millennium Pharmaceuticals, lecture fees from Janssen-Cilag, Ipsen and Sanofi-Aventis, and grant support from AstraZeneca. G. Attard is on The ICR rewards to inventors list of abiraterone acetate. No potential conflicts of interest were disclosed by the other authors.The Institute of Cancer Research authors are employees of the Section of Medicine that is supported by a Cancer Research UK programme grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (ref: C51/A7401). G. Attard is also supported by an NIHR clinical lectureship, a Welcome Trust Starter Grant for Clinical Lecturers and a young investigator award from the Prostate Cancer Foundation, Santa Monica, CA. J. Richards and A. Wingate were supported by Prostate Action, London, UK. W. Arlt is in receipt of a Medical Research Council (MRC) UK Strategic Biomarker Grant (G0801473). C. W. Hay was supported by the Chief Scientist's Office, Scottish Government. The authors also acknowledge NHS funding to the RMH NIHR Biomedical Research Centre. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	resistant prostate-cancer i clinical-trial antitumor-activity cyp17a1 inhibition xenograft model acetate cells pharmacokinetics glucocorticoids antiandrogen
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Alexander Smithson
Date Deposited:	04 Oct 2012 11:29
Last Modified:	11 Jul 2017 09:23
URI:	http://publications.icr.ac.uk/id/eprint/11918

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