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

CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗

• 批准号: 10442233
• 负责人: Nima Sharifi
• 金额: $ 36.83万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442233
• 关键词: Adrenal Glands; Androgen Receptor; Androgens; Antiandrogen Therapy; Binding; Biochemical Pathway; Bypass; CYP17A1 gene; Cancer Etiology; Castration; Cell Nucleus; Cessation of life; Cholesterol; Clinical Data; Clinical Research; Data; Detection; Discrimination; Disease; Drug resistance; Enzymes; Generations; Glucuronides; Goals; Hormonal; Hydroxysteroid Dehydrogenases; Hyperactivity; Lead; Malignant neoplasm of prostate; Mass Spectrum Analysis; Medical Castration; Medical Genetics; Metabolic; Methodology; Methods; Modeling; Natural regeneration; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphorylation Site; Physiological; Prostate; Prostate Cancer therapy; Resistance; Resistance development; Role; Serum; Stanolone; Steroid biosynthesis; Steroids; Testis; Testosterone; Work; abiraterone; advanced prostate cancer; androgen biosynthesis; androgen deprivation therapy; antagonist; castration resistant prostate cancer; cell growth; docetaxel; effective therapy; enzalutamide; enzyme activity; hormone therapy; inhibitor; innovation; intratumoral androgen; ionization; men; neoplastic cell; new therapeutic target; next generation; novel; phase III trial; therapy resistant; tumor

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.

概括 雄激素剥夺疗法（ADT），结合药物或手术去势，是长期存在的一线治疗方法 用于晚期前列腺癌。 3 期试验显示添加 4 种药物中的 1 种可带来深远的生存益处 （阿比特龙、多西紫杉醇、恩杂鲁胺或阿帕鲁胺）强化 ADT 治疗。不幸的是，药物 最终会发生抵抗，并且疾病几乎总是发展为致命的去势抵抗性前列腺 癌症（CRPC）。刺激雄激素受体（AR）的强效雄激素的再生是主要驱动力 抗药性，正如通过阻断雄激素合成所赋予的生存益处所证明的那样（例如，CYP17A1 抑制）或用强效拮抗剂直接阻断 AR。 5α-二氢睾酮（DHT）是主要的雄激素 与 AR 结合，CRPC 的临床研究一致表明，瘤内 DHT 升高至 生理相关水平。遗传临床证据现已证明 3β-羟基类固醇具有明确的作用 脱氢酶-1 (3βHSD1) 治疗耐药性。 ADT 期间 DHT 的再生是由于瘤内 雄激素从前体合成，可能源自胆固醇或利用的从头类固醇生成 肾上腺前体类固醇。 DHT 合成至少有 3 种可能的途径，它们都需要 CYP17A1 - 阿比特龙的药理靶点。没有雄激素合成的生化途径 已知可以规避 CYP17A1 的这一要求。此外，所有合成途径 睾酮 (T) 和/或 DHT 需要 3βHSD 酶活性。来自超过 800 名患者的临床数据显示 3βHSD1 的遗传性高度活跃形式与 CYP17A1 抑制的抗性相关，这导致我们 探究存在绕过下一代激素的独立于 CYP17A1 的途径的可能性 治疗封锁。我们已经确定了前列腺癌用作雄激素底物的氧甾醇 通过不受 CYP17A1 抑制影响的途径产生。相比之下，这条相同的途径是 3βHSD1 抑制作用被阻断。我们的进一步数据表明 3βHSD1 磷酸化对于 酶促激活。我们建议确定利用替代类固醇生成途径的作用 3βHSD1，从而规避了对 CYP17A1 的要求并能够抵抗下一代激素 疗法。我们将确定不依赖 CYP17A1 的雄激素合成在下一代抗- 雄激素治疗抵抗。此外，我们将识别和利用所需的磷酸化位点 3βHSD1 依赖性和 CYP17A1 独立的雄激素合成。影响：前列腺癌位居第二 美国男性癌症死亡的主要原因。我们的研究将为制定全新的方法铺平道路 雄激素合成的生化途径将定义治疗耐药性的主要机制和新的 治疗的目标。我们的工作具有高度创新性，因为这条途径是完全新颖的，我们将确定 雄激素合成的前体代谢物使用的方法，据我们所知，以前从未被使用过 用于此目的。