The androgen receptor (AR)-directed agents enzalutamide and abiraterone acetate are standard first-line therapies for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). These agents are generally well tolerated and effective at delaying disease progression, prolonging survival, and improving quality of life, but both drugs have limited durations of effectiveness. Patients with refractory disease typically have poor responses to subsequent AR-targeted agents, and there is currently no predictive biomarker that aids in the selection of a second-line therapy. Our group and others have identified upregulation of the glucocorticoid receptor (GR) as one mechanism of resistance to enzalutamide and abiraterone acetate. Our findings suggest that 1) GR may be a biomarker that can predict whether a patient will respond to enzalutamide or abiraterone and 2) blocking GR upregulation in enzalutamide- and abiraterone-resistant patients could result in tumor responses. In preliminary data, we show that isoforms of GR with variable N- termini can be expressed in metastatic CRPC, including one called GR?C that has increased capacity to promote enzalutamide resistance and is detectable in some patient-derived organoid cultures. It will be necessary to characterize GR?C and other GR isoforms in order to develop GR as a biomarker and a therapeutic target. Using a laboratory model of enzalutamide resistance, we have also found that GR expression is epigenetically modulated, and that treatment with an inhibitor of the BET family of proteins suppresses GR expression and restores enzalutamide sensitivity. Expanding on these findings, we will leverage our group's laboratory and clinical expertise to 1) investigate the role of GR isoforms in resistance to enzalutamide, 2) define the broader effects of BET inhibition across a range of preclinical models of prostate cancer, and 3) investigate the activity of a novel BET inhibitor in men with metastatic CRPC whose disease has progressed on enzalutamide or abiraterone acetate.

Public Health Relevance

Enzalutamide and abiraterone acetate are standard first-line treatments for men with prostate cancer that has spread and continued to grow despite injections that lower the level of the male hormone testosterone. While enzalutamide and abiraterone acetate are effective for most patients, tumors eventually become resistant and begin to grow again. In the laboratory, we have found that some tumors become resistant by increasing the level of a protein called GR, and we also found that an investigational drug called a BET inhibitor reduces GR levels in these tumors and causes them to shrink. This project will investigate whether different types of GR promote resistance to enzalutamide, how BET inhibitors work in prostate cancer cells, and whether BET inhibitors can shrink tumors in patients with advanced prostate cancer whose disease progressed on enzalutamide and abiraterone acetate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA092629-16
Application #
9148034
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2001-09-14
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Aras, Omer; Pearce, Gillian; Watkins, Adam J et al. (2018) An in-vivo pilot study into the effects of FDG-mNP in cancer in mice. PLoS One 13:e0202482
Sjoberg, Daniel D; Vickers, Andrew J; Assel, Melissa et al. (2018) Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men. Eur Urol 73:941-948
Vickers, Andrew J; Young-Afat, Danny A; Ehdaie, Behfar et al. (2018) Just-in-time consent: The ethical case for an alternative to traditional informed consent in randomized trials comparing an experimental intervention with usual care. Clin Trials 15:3-8
Assel, Melissa; Dahlin, Anders; Ulmert, David et al. (2018) Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening. Eur Urol 73:961-967
Han, SoHyun; Stoyanova, Radka; Lee, Hansol et al. (2018) Automation of pattern recognition analysis of dynamic contrast-enhanced MRI data to characterize intratumoral vascular heterogeneity. Magn Reson Med 79:1736-1744
Kinsella, Netty; Helleman, Jozien; Bruinsma, Sophie et al. (2018) Active surveillance for prostate cancer: a systematic review of contemporary worldwide practices. Transl Androl Urol 7:83-97
Vickers, Andrew J; Steineck, Gunnar (2018) Prognosis, Effect Modification, and Mediation. Eur Urol 74:243-245
Scher, Howard I; Graf, Ryon P; Schreiber, Nicole A et al. (2018) Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer. JAMA Oncol 4:1179-1186
Hieronymus, Haley; Murali, Rajmohan; Tin, Amy et al. (2018) Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife 7:
Luo, Jun; Attard, Gerhardt; Balk, Steven P et al. (2018) Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting. Eur Urol 73:715-723

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