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

基本信息

批准号：
10557156
负责人：
Nima Sharifi
金额：
$ 6.38万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2023-06-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557156
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 Goals Hormonal Hydroxysteroid Dehydrogenases Hyperactivity Malignant neoplasm of prostate Maps Mass Spectrum Analysis Medical Castration Medical Genetics Metabolic Methodology Methods Modeling Natural regeneration Pathway interactions Patients 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 enzalutamide enzyme activity hormone therapy inhibitor innovation intratumoral androgen ionization men neoplastic cell new therapeutic target next generation novel pharmacologic phase III trial therapy resistant tumor

项目摘要

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）进行了医学或手术cast割，是长期的前线治疗用于晚期前列腺癌。第三阶段试验表明，添加4个代理中的1个具有深远的生存优势（阿比罗酮，多西他赛，恩扎拉酰胺或阿apalutamide）加强用ADT治疗。不幸的是，药物抗药性最终发生，疾病几乎总是随着抗致命性cast割的前列腺的发展而发展癌症（CRPC）。刺激雄激素受体（AR）的潜在雄激素的再生是主要驱动因素耐药性，这是通过阻断雄激素合成所赋予的生存益处所证明的（例如，CYP17A1 抑制）或直接用潜在拮抗剂阻断AR。 5α-二氢睾丸激素（DHT）是主要的雄激素结合AR和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。遗传临床证据现在证明了3β-羟基固醇的明显作用在治疗耐药性中脱氢酶1（3βHSD1）。 DHT在ADT期间的再生是由于肿瘤内的雄激素合成的前体可能通过胆固醇或利用率从头类固醇生成起源肾上腺前体类固醇。至少有3种可能的DHT合成途径，所有这些都需要 CYP17A1-阿比罗酮的药物靶标。没有雄激素合成的生化途径是已知可以规避对CYP17A1的要求。此外，合成的所有途径睾丸激素（T）和/或DHT需要3βHSD酶活性。来自> 800名患者的临床数据 3βHSD1的一般多动激动形式与对CYP17A1抑制的抗性有关追求与CYP17A1无关的途径绕过下一代激素的可能性治疗封锁。我们已经确定了一种前列腺癌用作雄激素的氧化甲醇通过不受CYP17A1抑制的途径产生。相比之下，同样的途径是被3βHSD1抑制阻塞。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，因此规避了CYP17A1的需求，并具有对下一代激素的抗性疗法。我们将确定与CYP17A1非依赖性雄激素合成在下一代抗 - 雄激素疗法抗性。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：前列腺癌是第二种美国男性癌症死亡的主要原因。我们的研究将为绘制一个全新的方式铺平道路雄激素合成的生化途径将定义一种主要的治疗耐药性和新机制我们的工作具有很高的创新性，因为这条路完全是新颖的，我们将确定据我们所知，使用一种方法是用于此目的。