Prostate cancer depends on androgens and the androgen receptor (AR) for growth and progression. Metastatic tumors are usually initially treated with androgen deprivation therapy (ADT) by way of medical or surgical castration; however, tumors eventually recur as castration-resistant prostate cancer (CRPC), which progresses due to the intratumoral generation of testosterone and/or dihydrotestosterone (DHT) and AR stimulation. The intratumoral synthesis of potent androgens requires the activity of steroidogenic enzymes. In the prior project period, we identified the first example of a gain-of-function missense in a steroidogenic enzyme that increases what is otherwise the rate-limiting step of DHT synthesis from extragonadal precursor steroids and spurs the development of CRPC. This missense in 3?-hydroxysteroid dehydrogenase-1 (3?HSD1) is encoded by HSD3B1(1245C), a common germline variant. In the prior project period, we also discovered that patients with advanced prostate cancer who inherit the HSD3B1(1245C) genetic variant and receive ADT progress to CRPC more rapidly than patients who inherit the wild-type HSD3B1 enzyme, which has lower activity. Although clinical data across 4 patient cohorts now show that the HSD3B1(1245C) genetic variant is a predictive biomarker of resistance to ADT, the precise clinical utility of this biomarker remains uncertain. The overarching goal of this proposal is to determine how HSD3B1(1245C) should be utilized as a biomarker to identify patients who require more intensive upfront treatment and who are otherwise likely to progress more rapidly to lethal disease. As the HSD3B1(1245C) variant encodes for an enzyme that enables more rapid conversion of extragonadal precursors to DHT, we hypothesize that HSD3B1(1245C) is a predictive biomarker of sensitivity to drugs that block the synthesis or effects extragonadal androgens. We hypothesize that metabolism by 3?HSD1 is a class effect of steroidal CYP17A1 inhibitors, thus making non-steroidal CYP17A1 inhibitors or potent AR antagonists more suitable for treating patients who harbor the HSD3B1(1245C) variant. Finally, we hypothesize that intensification of treatment at the time of ADT in phase III clinical trials improves outcomes for patients with metastatic prostate cancer who inherit the HSD3B1(1245C) variant.
In Aim 1, we will determine if inheritance of the HSD3B1(1245C) variant is a predictive biomarker of response to non-steroidal CYP17A1 inhibitors or potent AR antagonists.
In Aim 2, we will identify whether susceptibility to 3?HSD metabolism is a class effect of steroidal CYP17A1 inhibitors and how this may determine response for patients who inherit the HSD3B1 variant.
In Aim 3, we will determine if patients with prostate cancer who inherit the HSD3B1(1245C) variant specifically benefit from more intensive upfront treatment at the time of ADT. If we are correct, the work in this proposal will change standard clinical practice for the treatment of prostate cancer.

Public Health Relevance

/Relevance Castration-resistant prostate cancer is the lethal form of prostate cancer and develops more rapidly for patients who inherit a germline gain-of-function in a steroidogenic enzyme we discovered in the previous project period. This proposal will determine whether patients who inherit this predictive biomarker of resistance to castration should be treated with more intensive upfront therapy and which specific therapies confer clinical benefit. We anticipate that this proposal is likely to change the standard of care for patients with prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA172382-07
Application #
9624734
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Song, Min-Kyung H
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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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
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; 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

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