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. Androgen deprivation therapy by depletion of gonadal testosterone is the upfront standard therapy for advanced disease. Metastatic disease almost invariably recurs as castration-resistant prostate cancer (CRPC), which is the lethal form of this disease. It is now clear that CRPC remains driven by the intratumoral synthesis of androgens, despite the depletion of serum testosterone. The survival benefit conferred by abiraterone acetate, which blocks CYP17A1 and was approved by the United States Food and Drug Administration in April 2011 for the treatment of CRPC, is the best evidence for the necessity of androgen synthesis in the progression of CRPC. Although the majority of patients with CRPC respond to abiraterone acetate, a subset do not have any initial response and nearly all responding tumors will eventually acquire resistance. A recent discovery that has been clinically validated has demonstrated that conversion from adrenal precursor steroids to dihydrotestosterone (DHT), the most potent androgen that drives CRPC progression, unexpectedly bypasses testosterone. This finding alters the current working model and suggests that 3?-hydroxysteroid dehydrogenase/isomerase (3?HSD) is a critical point of regulation in the synthesis of DHT and development of CRPC. The overarching hypothesis of this proposal is that a somatic gain-of-function mutation occurs in 3?HSD1 in the development of a subset of CRPC cases, increases mutant enzyme stability, augments DHT synthesis and confers resistance to abiraterone acetate.
In Aim 1, a pilot clinical study will be undertaken to determine how CRPC tumors harboring wild-type and mutant 3?HSD1 regulate flux to DHT and respond to abiraterone acetate.
In Aim 2, the validity of mutant 3?HSD1 as a potential pharmacologic target will be assessed.
In Aim 3, the consequences of wild-type and mutant 3?HSD1 interaction will be assessed. The ultimate anticipated benefit of this proposal is the identification of a first-in-clas gain-of-function mutation in a steroidogenic enzyme in CRPC that may serve as a biomarker of response or resistance to hormonal therapies, including abiraterone acetate. Furthermore, it is anticipated that similar to EGFR and BRAF mutations in lung cancer and melanoma, respectively, this work will validate mutant 3?HSD1 as a pharmacologic target for therapy in 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 elucidate the role of a novel mutation as a biomarker of response or resistance to hormonal therapy for CPRC. Furthermore, it will validate the mutant enzyme as a pharmacologic target for the treatment of CRPC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA172382-02
Application #
8551654
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Song, Min-Kyung H
Project Start
2012-09-26
Project End
2017-07-31
Budget Start
2013-08-29
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$309,159
Indirect Cost
$114,106
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
Sharifi, Nima (2013) Minireview: Androgen metabolism in castration-resistant prostate cancer. Mol Endocrinol 27:708-14