Elucidating a novel molecular biomarker for castration-resistant prostate cancer

项目摘要 前列腺癌的生长和发展依赖于雄激素和雄激素受体(AR)。 转移性肿瘤最初通常采用雄激素剥夺疗法(ADT)，通过药物或药物治疗 手术去势；然而，肿瘤最终复发为耐去势前列腺癌(CRPC)，它 肿瘤内产生睾酮和/或双氢睾酮(DHT)和AR的进展 刺激。强效雄激素的瘤内合成需要类固醇生成酶的活性。在……里面 在之前的项目期间，我们发现了第一例类固醇生成酶的功能获得错义。 这增加了从性腺外前体类固醇合成DHT的限速步骤和 这对中国铁建的发展起到了推动作用。3β-羟基类固醇脱氢酶-1(3βhsd1)中的这个错义是由 HSD3B1(1245C)，一种常见的生殖系变异。在之前的项目期间，我们还发现患有 遗传HSD3B1(1245C)基因变异并接受CRPC ADT进展的晚期前列腺癌 比遗传野生型HSD3B1酶的患者更快，HSD3B1酶的活性较低。虽然 4个患者队列的临床数据现在表明，HSD3B1(1245C)基因变异是一个预测生物标记物 对于ADT的耐药性，这种生物标记物的确切临床应用仍不确定。的首要目标是 这项建议是为了确定HSD3B1(1245C)应该如何用作生物标记物来识别 他们需要更密集的前期治疗，否则很可能会更快地发展为致命疾病。 由于HSD3B1(1245C)变异体编码一种酶，使其能够更快地转化为 DHT的性腺外前体，我们假设HSD3B1(1245C)是一个预测DHT敏感性的生物标志物 阻止合成或影响性腺外雄激素的药物。我们假设新陈代谢由3β热休克蛋白1 是一类甾体类细胞色素P17A1抑制剂，从而使非甾体类细胞色素P17A1抑制剂或强效AR 更适合治疗携带HSD3B1(1245C)变异的患者的拮抗剂。最后，我们假设 在第三阶段临床试验中，在ADT时加强治疗可以改善患者的预后 遗传HSD3B1(1245C)变异的转移性前列腺癌。在目标1中，我们将确定是否继承 HSD3B1(1245C)变异体是对非类固醇细胞色素P17A1抑制剂的反应的预测生物标志物 强大的AR拮抗者。在目标2中，我们将确定对3βhsd代谢的易感性是否是一种类别效应。 类固醇细胞色素P17A1抑制剂以及这可能如何决定遗传HSD3B1患者的反应 变种。在目标3中，我们将确定前列腺癌患者是否遗传了HSD3B1(1245C)变异 具体受益于ADT时更密集的前期治疗。如果我们是正确的，这里的工作 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.