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Science 324 (5928): 787-790

Copyright © 2009 by the American Association for the Advancement of Science

Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer

Chris Tran,1,* Samedy Ouk,5,* Nicola J. Clegg,1 Yu Chen,1,3 Philip A. Watson,1 Vivek Arora,1 John Wongvipat,1 Peter M. Smith-Jones,2 Dongwon Yoo,5 Andrew Kwon,1 Teresa Wasielewska,1 Derek Welsbie,6 Charlie Degui Chen,6,{dagger} Celestia S. Higano,7 Tomasz M. Beer,8 David T. Hung,9 Howard I. Scher,3 Michael E. Jung,5,{ddagger} Charles L. Sawyers1,4,{ddagger}

Abstract: Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.

1 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3 Genitourinary Oncology Service, Division of Solid Tumor Oncology and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4 Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
6 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
7 Division of Oncology, Departments of Medicine and Urology, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
8 OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
9 Medivation, Inc., 201 Spear Street, San Francisco, CA 94105, USA.

* These authors contributed equally to this work.

{dagger} Present address: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

{ddagger} To whom correspondence should be addressed. E-mail: sawyersc{at}mskcc.org; jung{at}chem.ucla.edu

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Prediction of Survival following First-Line Chemotherapy in Men with Castration-Resistant Metastatic Prostate Cancer.
A. J. Armstrong, E. Garrett-Mayer, R. de Wit, I. Tannock, and M. Eisenberger (2010)
Clin. Cancer Res. 16, 203-211
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Clarification of NICE Guidance on Prostate Cancer.
D. E. Neal, J. McLoughlin, J. B. Anderson, D. P. Fawcett, and R. C. Kockelbergh (2009)
Journal of Clinical Urology 2, 219-223
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MUC1 oncoprotein is a druggable target in human prostate cancer cells.
M. D. Joshi, R. Ahmad, L. Yin, D. Raina, H. Rajabi, G. Bubley, S. Kharbanda, and D. Kufe (2009)
Mol. Cancer Ther. 8, 3056-3065
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Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer.
K. E. Knudsen and H. I. Scher (2009)
Clin. Cancer Res. 15, 4792-4798
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Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.
J. D. Joseph, B. M. Wittmann, M. A. Dwyer, H. Cui, D. A. Dye, D. P. McDonnell, and J. D. Norris (2009)
PNAS 106, 12178-12183
   Abstract »    Full Text »    PDF »

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