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：
9900724
负责人：
Nima Sharifi
金额：
$ 38.18万
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/9900724
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 biomarker performance castration resistant prostate cancer clinical practice cohort docetaxel gain of function genetic variant hormone therapy improved outcome inhibitor/antagonist 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.

项目摘要前列腺癌取决于雄激素和雄激素受体（AR）的生长和进展。通常最初通过医学或手术cast割；然而，肿瘤最终会作为耐castration的前列腺癌（CRPC）复发，这由于肿瘤内产生睾丸激素和/或二氢睾丸激素（DHT）和AR的进展刺激。潜在雄激素的肿瘤内合成需要类固醇生成酶的活性。在前期项目期间，我们确定了类固醇生成酶中功能障碍错义的第一个例子这增加了否则是从外部前体类固醇和马刺CRPC的发展。 3β-羟基甾体脱氢酶1（3βHSD1）中的这种错义由 HSD3B1（1245c），一种常见的种系变体。在以前的项目期间，我们还发现继承HSD3B1（1245c）遗传变异并接受ADT的高级前列腺癌比继承野生型HSD3B1酶的患者的速度更快，该酶的活性较低。虽然现在，四个患者队列的临床数据显示，HSD3B1（1245c）遗传变异是一种预测性生物标志物具有对ADT的抵抗力，该生物标志物的精确临床实用性仍然不确定。总体目标该建议是确定如何将HSD3B1（1245C）用作生物标志物来识别患者需要更深入的前期治疗，否则他们可能会更快地发展为致命疾病。如HSD3B1（1245C）变体所编码的酶，该酶可以更快地转化在DHT的外部前体，我们假设HSD3B1（1245C）是对敏感性的预测生物标志物阻断合成或作用的药物。我们假设3βHSD1的代谢是类固醇CYP17A1抑制剂的类效果拮抗剂更适合治疗携带HSD3B1（1245c）变体的患者。最后，我们假设在III期临床试验中ADT时的治疗加剧可改善继承HSD3B1（1245c）变体的转移性前列腺癌。在AIM 1中，我们将确定是否继承 HSD3B1（1245C）变体的变体是对非甾体cyp17a1抑制剂或反应的预测生物标志物潜在的AR拮抗剂。在AIM 2中，我们将确定对3βHSD代谢的敏感性是否是类效应类固醇CYP17A1抑制剂，以及如何确定继承HSD3B1的患者的反应变体。在AIM 3中，我们将确定继承HSD3B1（1245c）变体的前列腺癌患者是否是否特别是在ADT时更深入的前期治疗中受益。如果我们是正确的，那么这项工作提案将改变治疗前列腺癌的标准临床实践。