Elucidating a novel molecular biomarker for castration-resistant prostate cancer

项目摘要 前列腺癌的生长和进展依赖于雄激素和雄激素受体（AR）。 转移性肿瘤通常最初通过药物或化疗的方式用雄激素剥夺疗法（ADT）治疗。 然而，肿瘤最终复发为去势抵抗性前列腺癌（CRPC）， 由于肿瘤内产生睾酮和/或双氢睾酮（DHT）和AR而导致的进展 刺激.肿瘤内合成有效的雄激素需要类固醇生成酶的活性。在 在前一个项目期间，我们确定了类固醇生成酶中功能获得性错义的第一个例子 这增加了从性腺外前体类固醇合成DHT的限速步骤， 促进了CRPC的发展。3β-羟基类固醇脱氢酶-1（3β HSD 1）的这种错义由以下基因编码： HSD 3B 1（1245 C），一种常见的生殖系变异体。在上一个项目期间，我们还发现， 遗传HSD 3B 1（1245 C）遗传变异并接受ADT治疗的晚期前列腺癌进展为CRPC 比遗传了活性较低的野生型HSD 3B 1酶的患者更快。虽然 目前，4个患者队列的临床数据显示，HSD 3B 1（1245 C）遗传变异是一种预测性生物标志物， 由于对ADT的耐药性，该生物标志物的精确临床效用仍不确定。的首要目标 该提案旨在确定如何将HSD 3B 1（1245 C）用作生物标志物，以识别 需要更密集的前期治疗，否则可能会更快地发展为致命疾病。 由于HSD 3B 1（1245 C）变体编码能够更快速地转化H2 O2的酶， 性腺外前体的DHT，我们假设HSD 3B 1（1245 C）是一个预测生物标志物的敏感性， 阻断合成或影响性腺外雄激素的药物。我们假设3β HSD 1的代谢 是甾体CYP 17 A1抑制剂的类效应，因此使非甾体CYP 17 A1抑制剂或强效AR 更适合于治疗携带HSD 3B 1（1245 C）变体的患者的拮抗剂。最后，我们假设 III期临床试验中ADT时的强化治疗可改善以下患者的结局： 转移性前列腺癌遗传HSD 3B 1（1245 C）变异。在目标1中，我们将确定是否继承 HSD 3B 1（1245 C）变异体是对非甾体CYP 17 A1抑制剂应答的预测性生物标志物，或 有效的AR拮抗剂。在目标2中，我们将确定对3βHSD代谢的易感性是否为类效应 甾体CYP 17 A1抑制剂以及这如何决定遗传了HSD 3B 1的患者的反应 变量。在目标3中，我们将确定是否患有前列腺癌的患者谁继承了HSD 3B 1（1245 C）变异， 特别是在ADT时从更密集的前期治疗中受益。如果我们是正确的，这方面的工作 该提案将改变前列腺癌治疗的标准临床实践。

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.