.. 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

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA163227-01A1
Application #
8475911
Study Section
Project Start
2013-05-24
Project End
2018-04-30
Budget Start
2013-05-24
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$292,751
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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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

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