Prostate cancer is the most common cause of cancer and second leading cause of cancer death for men in the United States. Localized disease is potentially curable with radiation or surgery;however, advanced disease remains incurable. Depletion of gonadal testosterone is the upfront standard therapy for advanced disease. Unfortunately, metastatic disease almost always recurs as castration-resistant prostate cancer (CRPC), which is generally the lethal form of this disease. Despite depletion of gonadal testosterone, CRPC remains driven by intratumoral synthesis of androgens. The survival benefit conferred by abiraterone acetate, which blocks CYP17A1, is the best evidence for the necessity of androgen synthesis in the progression of CRPC. Initial or acquired resistance to abiraterone acetate, which was approved by the United States Food and Drug Administration in April 2011 for the treatment of CRPC, has now become the next hurdle to overcome. Recent studies have shown that synthesis of dihydrotestosterone (DHT), the most potent androgen that drives CRPC progression, unexpectedly bypasses testosterone. This finding alters the landscape of potential drug targets and suggests that 3?-hydroxysteroid dehydrogenase/isomerase (3?HSD) is a potentially important and viable pharmacologic target. The overarching hypothesis of this proposal is that effective pharmacologic inhibition of 3?HSD will be an effective treatment for CRPC and tumors that are resistant to abiraterone acetate.
In Aim 1, the role and requirement of 3?HSD1 and 3?HSD2 expression for the development and progression of CRPC will be defined.
In Aim 2, the effect(s) of abiraterone acetate on the conversion from dehydroepiandrosterone to androstenedione by 3?HSD1 and 3?HSD2 will be characterized.
In Aim 3, a series of steroidal azoles will be synthesized and candidate inhibitors of recombinant 3?HSD1 and 3?HSD2 will be identified, which also inhibit CYP17A1. The ultimate anticipated benefit of this proposal is the development of new and improved approaches to the treatment of men with CRPC.

Public Health Relevance

Castration-resistant prostate cancer (CRPC), the lethal form of this disease, is the second leading cause of cancer death for men in the United States and is therefore a major public health problem. This proposal will identify the specific role of two isoenzymes required for CRPC progression, define their suitability as potential drug targets and identify candidate compounds that may serve as lead candidates for pharmacologic therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA168899-01A1
Application #
8442754
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$340,899
Indirect Cost
$96,603
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Sharifi, Nima (2015) Steroid sidestep: evading androgen ablation by abiraterone. Clin Cancer Res 21:1240-2
Chang, K-H; Ercole, C E; Sharifi, N (2014) Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences. Br J Cancer 111:1249-54
Sharifi, Nima (2013) Mechanisms of androgen receptor activation in castration-resistant prostate cancer. Endocrinology 154:4010-7
Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara et al. (2013) A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154:1074-84