CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy

总结 雄激素剥夺疗法（ADT），与药物或手术去势，是长期的一线治疗 治疗晚期前列腺癌3期试验显示，添加4种药物中的1种可获得显著的生存获益 （阿比特龙、多西他赛、Enzalutamide或apalutamide）加强ADT治疗。不幸的是，药物 最终会产生耐药性，疾病几乎总是进展为致命的去势抵抗性前列腺疾病。 癌症（CRPC）。刺激雄激素受体（AR）的强效雄激素的再生是一个主要的驱动力 的抗性，如通过阻断雄激素合成所赋予的存活益处所证明的（例如，CYP17A1 抑制）或用有效拮抗剂直接阻断AR。5α-双氢睾酮（5α-dihydrotestosterone，DHT）是主要的雄激素 CRPC的临床研究一致表明，瘤内DHT升高至 生理相关水平。遗传临床证据现在证明了3β-羟基类固醇的明确作用 脱氢酶-1（3β HSD 1）在处理抗性中的作用。ADT期间DHT的再生是由于肿瘤内 来自前体的雄激素合成，可能通过胆固醇或利用的从头类固醇合成而产生 肾上腺前体类固醇至少有3种可能的途径合成DHT，它们都需要 CYP 17 A1-阿比特龙的药理学靶点。没有雄激素合成的生化途径， 已知规避了CYP 17 A1的这一要求。此外，用于合成 睾酮（T）和/或DHT需要3βHSD酶活性。来自> 800名患者的临床数据显示 3β HSD 1的遗传性高活性形式与对CYP 17 A1抑制的抗性有关，这使我们 寻求CYP 17 A1独立途径存在的可能性，绕过下一代激素 治疗封锁。我们已经确定了一种氧固醇，前列腺癌用作雄激素的底物 通过对CYP 17 A1抑制不敏感的途径产生。相比之下， 3β-HSD 1抑制剂阻断。我们进一步的数据表明，3β HSD 1磷酸化是绝对必要的， 酶促活化我们建议确定替代类固醇生成途径的作用， 3β HSD 1，从而避免了对CYP 17 A1的需求，并使其对下一代激素产生耐药性 治疗我们将确定CYP 17 A1非依赖性雄激素合成在下一代抗肿瘤治疗中的作用。 雄激素治疗抵抗。此外，我们将确定和利用磷酸化位点所需的， 3β HSD 1依赖性和CYP 17 A1非依赖性雄激素合成。影响：前列腺癌是第二位 美国男性癌症死亡的主要原因。我们的研究将为制定一个全新的 雄激素合成的生化途径，将定义治疗抗性的主要机制和新的 治疗的目标我们的工作是高度创新的，因为这条途径是完全新颖的，我们将确定 前体代谢物的雄激素合成使用的方法，据我们所知， 用于此目的。

Summary Androgen deprivation therapy (ADT), with medical or surgical castration, is the long-standing frontline treatment for advanced prostate cancer. Phase 3 trials show a profound survival benefit for addition of 1 of 4 agents (abiraterone, docetaxel, enzalutamide or apalutamide) to intensify treatment with ADT. Unfortunately, drug resistance eventually occurs, and disease almost always progresses as lethal castration-resistant prostate cancer (CRPC). Regeneration of potent androgens that stimulate the androgen receptor (AR) is a major driver of resistance, as is evidenced by the survival benefit conferred by blocking androgen synthesis (e.g., CYP17A1 inhibition) or directly blocking AR with potent antagonists. 5α-dihydrotestosterone (DHT) is the major androgen that binds AR, and clinical studies of CRPC have consistently shown that intratumoral DHT is elevated to physiologically relevant levels. Genetic clinical evidence now demonstrates a clear role for 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) in treatment resistance. The regeneration of DHT during ADT is due to intratumoral androgen synthesis from precursors that may originate via de novo steroidogenesis from cholesterol or utilization of adrenal precursor steroids. There are at least 3 possible pathways to DHT synthesis which all require CYP17A1 - the pharmacologic target of abiraterone. No biochemical pathway of androgen synthesis is known to circumvent this requirement for CYP17A1. Further, all pathways for the synthesis of testosterone (T) and/or DHT require 3βHSD enzymatic activity. Clinical data from > 800 patients showing that a genetically hyperactive form of 3βHSD1 is associated with resistance to CYP17A1 inhibition led us to pursue the possibility that a CYP17A1-independent pathway exists that bypasses next-generation hormonal therapy blockade. We have identified an oxysterol that prostate cancer uses as a substrate for androgen generation via a pathway that is impervious to CYP17A1 inhibition. In contrast, this same pathway is blocked by 3βHSD1 inhibition. Our further data suggest that 3βHSD1 phosphorylation is absolutely essential for enzymatic activation. We propose to determine the role of alternative steroidogenesis pathways that utilize 3βHSD1, thus circumventing the requirement for CYP17A1 and enabling resistance to next-generation hormonal therapies. We will determine the role of CYP17A1-independent androgen synthesis in next-generation anti- androgen therapy resistance. Furthermore, we will identify and exploit phosphorylation sites that are required for 3βHSD1-dependent and CYP17A1-independent androgen synthesis. Impact: Prostate cancer is the second leading cause of cancer death in U.S. men. Our studies will pave the way to mapping out an entirely new biochemical pathway of androgen synthesis that will define a major mechanism of treatment resistance and new targets for therapy. Our work is highly innovative because this pathway is entirely novel, and we will identify precursor metabolites for androgen synthesis using an approach that, to our knowledge, has not previously been utilized for this purpose.