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 #
5R01CA172382-03
Application #
8727994
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
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Almassi, Nima; Reichard, Chad; Li, Jianbo et al. (2018) HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer. JAMA Oncol 4:554-557
Zhu, Ziqi; Chung, Yoon-Mi; Sergeeva, Olga et al. (2018) Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging. J Biol Chem 293:17829-17837
Ko, Hyun-Kyung; Berk, Michael; Chung, Yoon-Mi et al. (2018) Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer. Cell Rep 22:809-819
Alyamani, Mohammad; Emamekhoo, Hamid; Park, Sunho et al. (2018) HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J Clin Invest 128:3333-3340
Hettel, Daniel; Zhang, Ao; Alyamani, Mohammad et al. (2018) AR Signaling in Prostate Cancer Regulates a Feed-Forward Mechanism of Androgen Synthesis by Way of HSD3B1 Upregulation. Endocrinology 159:2884-2890
Gao, Xiaomei; Dai, Charles; Huang, Shengsong et al. (2018) Functional silencing of HSD17B2 in prostate cancer promotes disease progression. Clin Cancer Res :
Hearn, Jason W D; Xie, Wanling; Nakabayashi, Mari et al. (2018) Association of HSD3B1 Genotype With Response to Androgen-Deprivation Therapy for Biochemical Recurrence After Radiotherapy for Localized Prostate Cancer. JAMA Oncol 4:558-562
Alyamani, Mohammad; Li, Zhenfei; Upadhyay, Sunil K et al. (2017) Development and validation of a novel LC-MS/MS method for simultaneous determination of abiraterone and its seven steroidal metabolites in human serum: Innovation in separation of diastereoisomers without use of a chiral column. J Steroid Biochem Mol Biol 172:231-239
Li, Jianneng; Alyamani, Mohammad; Zhang, Ao et al. (2017) Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer. Elife 6:
Dai, Charles; Chung, Yoon-Mi; Kovac, Evan et al. (2017) Direct Metabolic Interrogation of Dihydrotestosterone Biosynthesis from Adrenal Precursors in Primary Prostatectomy Tissues. Clin Cancer Res 23:6351-6362

Showing the most recent 10 out of 21 publications