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

摘要 雄激素剥夺疗法(Adt)，通过药物或手术去势，是长期存在的一线治疗方法。 治疗晚期前列腺癌。3期试验显示，添加4种药物中的1种对生存有显著益处 (阿比特龙、多西紫杉醇、苯扎鲁胺或阿帕鲁胺)强化ADT治疗。不幸的是，毒品 耐药性最终发生，疾病几乎总是以致命的去势抵抗前列腺癌的形式进展。 癌症(CRPC)。刺激雄激素受体(AR)的有效雄激素的再生是主要驱动力 抗药性，阻止雄激素合成(例如，CYP17A1)带来的生存益处证明了这一点 抑制)或用有效的拮抗剂直接阻断AR。5-二氢睾酮(5-α-diwater testerone，dht)是主要的雄激素 它与AR结合，CRPC的临床研究一直表明，肿瘤内DHT升高到 生理上相关的水平。遗传临床证据现在表明3-β-羟基类固醇具有明确的作用 脱氢酶-1(3β-HSD1)与抗药性。ADT期间DHT的再生是由于肿瘤内的原因 来自前体的雄激素合成，可能起源于胆固醇或利用的从头合成类固醇 肾上腺前体类固醇。DHT的合成至少有3条可能的途径，它们都需要 细胞色素P17A1-阿比特龙的药理靶点。没有雄激素合成的生化途径 已知可以绕过这一要求的CYP17A1。此外，合成的所有途径 睾酮(T)和/或双羟色胺需要3β的HSD酶活性。来自&gt；800患者的临床数据显示 一种基因上高度活跃的3βhsd1与对细胞色素P17A1抑制的抗性有关，这让我们 探索存在绕过下一代荷尔蒙的不依赖于CYP17A1的途径的可能性 治疗封锁。我们已经确定了一种前列腺癌用来作为雄激素底物的氧合固醇。 通过一条不受CYP17A1抑制的途径产生。相比之下，同样的途径是 被3β热休克蛋白1抑制。我们的进一步数据表明，3β热休克蛋白1的磷酸化是绝对必要的 酶促激活。我们建议确定替代类固醇生成途径的作用，这些途径利用 3βhsd1，从而绕过了对CYP17A1的要求，使其能够抵抗下一代激素 治疗。我们将确定CYP17A1非依赖性雄激素合成在下一代抗肿瘤中的作用。 雄激素治疗抵抗。此外，我们将确定和利用所需的磷酸化位点 3CYP17A1非依赖和β依赖的雄激素合成。影响：前列腺癌排在第二位 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耐药的主要机制和新的 治疗的目标。我们的工作具有很高的创新性，因为这条途径是完全新颖的，我们将确定 使用一种方法合成雄激素的前体代谢物，据我们所知，这种方法以前从未 用于此目的的。

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.