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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.

总结