Elucidating a novel molecular biomarker for castration-resistant prostate cancer

总结 前列腺癌是美国男性癌症死亡的第二大原因。晚期癌症的一线治疗 前列腺癌的治疗方法是雄激素剥夺疗法（ADT），其已经成为护理标准约80年。最近 实践改变的数据已经证明，当ADT强化时， 强化的原因尚不清楚。无论如何，转移性疾病几乎总是进展为去势抵抗 前列腺癌（CRPC）。新的CRPC治疗的主要限制是基于先前的CRPC治疗选择患者。 治疗，而不是他们的遗传和疾病驱动的分子过程。我们之前的主要发现 项目期间包括明确和可重现的临床证据，表明"肾上腺允许" HSD3B1（1245C） 种系变体编码3 β-羟基类固醇脱氢酶-1（3 β HSD1）的功能获得性错义， 性腺外合成5 α-二氢睾酮限速酶 类固醇前体这种肾上腺允许的HSD3B1是激素治疗的遗传和代谢驱动因素 阻力在这次更新申请中，我们建议确定 HSD3B1（1245C）变异体的遗传，并将其用作定制去势的生物标志物- 对个体患者的遗传学和肿瘤具有抗性和去势敏感性的前列腺癌治疗 生物学我们假设生殖系HSD3B1（1245C）变异是一种预测性生物标志物， 以确定哪些患者将受益于前期肾上腺雄激素消融。我们的初步数据显示， BMX对3 β HSD1磷酸化的抑制将是治疗性的--直接治疗性抑制3 β HSD1， 患有肾上腺允许性HSD3B1的男性应该逆转由以下因素引起的不良生物学和临床结果： CRPC中的性腺外雄激素生物合成。我们的数据还表明，在强化激素治疗后， HSD3B1遗传是全身代谢影响的决定因素，包括在一些男性中观察到的不良影响， 而不是其他人。我们提出的概念的潜在临床后果是深远的，因为它们 将生殖系疾病驱动代谢驱动因素与治疗机制结合起来，以逆转不良结局。 目的1：确定肾上腺素允许的HSD3B1（1245C）等位基因的遗传是否是一个预测性因素。 在ADT基础上添加阿比特龙治疗非转移性去势敏感性前列腺获益改善的生物标志物 癌我们将分析959名参加STAMPEDE试验的男性的生殖系DNA。目标2：定义 磷酸化在3 β HSD1活化中的作用，并确定BMX在DHEA转化为 下游强有力的雄激素。我们将确定BMX激酶是否是3 β HSD1磷酸化所必需的 和细胞活化，并在概念验证临床试验中测试其功效。目标3：确定机制 在接受强化激素治疗的男性中，HSD3B1遗传与循环代谢物之间存在联系。 调节这些循环代谢物的机制很可能是肝脏代谢的功能，因此， 我们将测试HSD3B1基因型的作用是否通过性类固醇信号或胆汁酸信号发生。

SUMMARY Prostate cancer is the second leading cause of cancer death in U.S. men. The frontline treatment for advanced prostate cancer is androgen deprivation therapy (ADT), which has been the standard of care for ~80 years. Recent practice-changing data have demonstrated a survival benefit when ADT is intensified, but the treatment choice for intensification is unclear. Regardless, metastatic disease almost always progresses as castration-resistant prostate cancer (CRPC). A major limitation of new CRPC treatments is that patients are selected based on prior therapies instead of their genetics and disease-driving molecular processes. Essential findings from our previous project period include clear and reproducible clinical evidence that an “adrenal-permissive” HSD3B1(1245C) germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), the rate-limiting steroidogenic enzyme for synthesis of 5α-dihydrotestosterone (DHT) from extragonadal precursor steroids. This adrenal-permissive HSD3B1 is a genetic and metabolic driver of hormone therapy resistance. In this renewal application, we propose to determine the mechanisms and clinical significance of inheritance of the HSD3B1(1245C) variant and move toward its use as a biomarker to tailor castration- resistant and castration-sensitive prostate cancer treatment to the individual patient's genetics and tumor biology. We hypothesize that the germline HSD3B1(1245C) variant is a predictive biomarker that will allow us to identify patients who will benefit from upfront adrenal androgen ablation. Our preliminary data indicate that BMX inhibition of 3βHSD1 phosphorylation will be therapeutic – direct therapeutic inhibition of 3βHSD1 for men with the adrenal-permissive HSD3B1 should reverse the adverse biology and clinical outcomes conferred by extragonadal androgen biosynthesis in CRPC. Our data also indicate that after intensified hormonal therapy, HSD3B1 inheritance is a determinant of systemic metabolic effects, including adverse effects seen in some men, but not others. The potential clinical consequences of the concepts we propose are profound because they couple a germline disease-driving metabolic driver to therapeutic mechanisms for reversal of poor outcomes. Aim 1: Determine whether inheritance of the adrenal-permissive HSD3B1(1245C) allele is a predictive biomarker of improved benefit from adding abiraterone to ADT for non-metastatic castration-sensitive prostate cancer. We will analyze germline DNA available from 959 men enrolled in the STAMPEDE trial. Aim 2: Define the role of phosphorylation in 3βHSD1 activation and determine the role of BMX in the conversion of DHEA to downstream potent androgens. We will determine if the BMX kinase is essential for 3βHSD1 phosphorylation and cellular activation and test its efficacy in a proof-of-concept clinical trial. Aim 3: Determine the mechanistic link between HSD3B1 inheritance and circulating metabolites in men undergoing intensive hormonal therapy. The mechanisms that regulate these circulating metabolites are most likely a function of hepatic metabolism, so we will test whether the effects of HSD3B1 genotype occur via sex steroid signaling or bile acid signaling.