Currently available AR antagonists such as bicalutamide have limited activity in castration-resistant prostate cancer (CRPC). Mechanistic studies have shown that the bicalutamide liganded AR can accumulate in the nucleus and bind to chromatin, but that it does not effectively recruit coactivator proteins and instead can recruit the corepressor proteins NCoR and SMRT. This ability to mediate chromatin binding may be an "Achilles Heal" of these agents, as it could facilitate their acquisition of weak or possibly strong agonist activity in CRPC. In contrast to these currently available antagonists, MDV3100 does not enhance nuclear localization or simulate chromatin binding, and recently reported phase III trial results show that MDV3100 can prolong survival in CRPC. These findings likely will lead to FDA approval of MDV3100 in the near future, arming medical oncologists with two new agents (abiraterone and MDV3100) that can effectively suppress AR activity in CRPC. Therefore, it is now critical to understand in detail mechanisms of action for MDV3100 and related AR antagonists under development, to determine how they might best be used in conjunction with abiraterone, and to identify mechanisms of intrinsic and acquired resistance. Our overall objectives in this proposal are to understand how MDV3100 and functionally related AR antagonists interfere with AR binding to chromatin, and to identify mechanisms of resistance. Our recent studies have shown that phosphorylation of serine 81 (S81) in the AR N-terminal domain is critical for stable binding of AR to chromatin. Moreover, our data indicate that the primary mechanism of action of MDV3100 is to prevent chromatin binding, and that MDV3100 interferes with a S81 dependent step in AR chromatin binding. Based on these findings, our general approach is to determine the molecular basis for S81 dependent AR binding to chromatin (Aim 1) and to determine how MDV3100 and functionally related antagonists interfere with this binding (Aim 2). We will then evaluate candidate mechanisms of MDV3100 resistance in cell line models (Aim 2), and in xenograft models and clinical samples (Aim 3).

Public Health Relevance

The likely FDA approval of MDV3100 will arm oncologists with two new agents (abiraterone and MDV3100) that can suppress AR activity in CRPC, but patients invariably relapse and resistance mechanisms are unknown. Tis proposal will determine in detail the mechanisms of action for MDV3100 and functionally related AR antagonists under development, and identify mechanisms of .intrinsic and acquired resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Damodarasamy, Mamatha; Vernon, Robert B; Chan, Christina K et al. (2015) Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell Dev Biol Anim 51:50-8
Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai et al. (2015) Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 21:1273-80
Sowalsky, Adam G; Xia, Zheng; Wang, Liguo et al. (2015) Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106
Tamae, Daniel; Mostaghel, Elahe; Montgomery, Bruce et al. (2015) The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Interact 234:332-8
Jehle, Katja; Cato, Laura; Neeb, Antje et al. (2014) Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif. J Biol Chem 289:8839-51
Hsieh, Chen-Lin; Fei, Teng; Chen, Yiwen et al. (2014) Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A 111:7319-24
Cao, Bo; Qi, Yanfeng; Zhang, Guanyi et al. (2014) Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5:1646-56
He, Housheng Hansen; Meyer, Clifford A; Hu, Sheng'en Shawn et al. (2014) Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification. Nat Methods 11:73-8
Penning, Trevor M (2014) Androgen biosynthesis in castration-resistant prostate cancer. Endocr Relat Cancer 21:T67-78
Thadani-Mulero, Maria; Portella, Luigi; Sun, Shihua et al. (2014) Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 74:2270-82

Showing the most recent 10 out of 24 publications