.. 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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Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng et al. (2016) Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533:547-51
Kumar, Akash; Coleman, Ilsa; Morrissey, Colm et al. (2016) Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 22:369-78
Gao, Shuai; Gao, Yanfei; He, Housheng Hansen et al. (2016) Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein. Cell Rep 17:966-976
Penning, Trevor M; Tamae, Daniel (2016) Current advances in intratumoral androgen metabolism in castration-resistant prostate cancer. Curr Opin Endocrinol Diabetes Obes 23:264-70
Asangani, Irfan A; Wilder-Romans, Kari; Dommeti, Vijaya L et al. (2016) BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer. Mol Cancer Res 14:324-31
Wu, Yu; Schoenborn, Jamie R; Morrissey, Colm et al. (2016) High-Resolution Genomic Profiling of Disseminated Tumor Cells in Prostate Cancer. J Mol Diagn 18:131-43
Mostaghel, Elahe A; Zhang, Ailin; Plymate, Stephen (2016) UDP-glucuronosyltransferase Enzymes in Prostate Cancer Progression: Is Only Androgen Catabolism Involved? Eur Urol 69:610-2
Groner, Anna C; Cato, Laura; de Tribolet-Hardy, Jonas et al. (2016) TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer. Cancer Cell 29:846-58

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