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Elucidating a novel molecular biomarker for castration-resistant prostate cancer

阐明去势抵抗性前列腺癌的新型分子生物标志物

基本信息

批准号：
10372921
负责人：
Nima Sharifi
金额：
$ 37.47万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372921
关键词：
AR gene Alleles Androgen Metabolism Androgen Receptor Androgens Biological Markers CYP17A1 gene Castration Clinical Clinical Data Clinical Management Clinical Research Clinical Trials Development Disease Enzymes Generations Genetic Polymorphism Goals Growth Hydroxysteroid Dehydrogenases Inherited Malignant Neoplasms Malignant neoplasm of prostate Medical Castration Metabolic Metabolism Metastatic Prostate Cancer Neoadjuvant Therapy Neoplasm Metastasis Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase III Clinical Trials Predisposition Prostate Cancer therapy Publishing Receptor Signaling Resistance Resistance development Signal Transduction Stanolone Steroids Testosterone Time Tissues Variant Work advanced prostate cancer adverse outcome androgen deprivation therapy antagonist biomarker performance castration resistant prostate cancer clinical practice cohort docetaxel gain of function genetic variant hormone therapy improved outcome inhibitor molecular marker novel patient response predictive marker response response biomarker standard of care steroid metabolism treatment duration tumor

项目摘要

Project Summary 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 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) 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 3βHSD1 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 3βHSD 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.

项目总结