Research Project 4:Investigating and targeting the glucocorticoid receptor (GR) in enzalutamide- and abiraterone-resistant prostate cancer

研究项目 4：研究和靶向恩杂鲁胺和阿比特龙耐药性前列腺癌中的糖皮质激素受体 (GR)

• 批准号: 9148034
• 负责人: CHARLES L. SAWYERS
• 金额: $ 18.06万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-14 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148034
• 关键词: Acetates; Androgen Receptor; Basic Science; Biological Markers; Biopsy; CRISPR/Cas technology; Cancer Patient; Cell Line; ChIP-seq; Clinical; Clinical Sciences; Data; Detection; Development; Disease; Disease Progression; Doctor of Philosophy; Drug resistance; Effectiveness; Epigenetic Process; Evaluation; Gene Expression Profile; Generations; Glucocorticoid Receptor; Hematologic Neoplasms; Hormones; Initiator Codon; Injection of therapeutic agent; Investigational Drugs; Laboratories; Lead; Length; Malignant neoplasm of prostate; Methods; Modeling; Monoclonal Antibodies; Multicenter Trials; N-terminal; Organoids; Output; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pre-Clinical Model; Protein Family; Protein Isoforms; Proteins; Quality of life; Refractory Disease; Research Project Grants; Resistance; Role; Sampling; Technology; Testosterone; Tissue Sample; Translation Initiation; Up-Regulation; Validation; Work; Xenograft procedure; abiraterone; abstracting; castration resistant prostate cancer; improved; inhibitor/antagonist; insight; male; men; novel; predictive marker; prostate cancer cell; prostate cancer model; receptor expression; receptor upregulation; research study; resistance mechanism; response; targeted agent; therapeutic target; tumor

Project Summary/Abstract The androgen receptor (AR)-directed agents enzalutamide and abiraterone acetate are standard first-line therapies for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). These agents are generally well tolerated and effective at delaying disease progression, prolonging survival, and improving quality of life, but both drugs have limited durations of effectiveness. Patients with refractory disease typically have poor responses to subsequent AR-targeted agents, and there is currently no predictive biomarker that aids in the selection of a second-line therapy. Our group and others have identified upregulation of the glucocorticoid receptor (GR) as one mechanism of resistance to enzalutamide and abiraterone acetate. Our findings suggest that 1) GR may be a biomarker that can predict whether a patient will respond to enzalutamide or abiraterone and 2) blocking GR upregulation in enzalutamide- and abiraterone-resistant patients could result in tumor responses. In preliminary data, we show that isoforms of GR with variable N- termini can be expressed in metastatic CRPC, including one called GRαC that has increased capacity to promote enzalutamide resistance and is detectable in some patient-derived organoid cultures. It will be necessary to characterize GRαC and other GR isoforms in order to develop GR as a biomarker and a therapeutic target. Using a laboratory model of enzalutamide resistance, we have also found that GR expression is epigenetically modulated, and that treatment with an inhibitor of the BET family of proteins suppresses GR expression and restores enzalutamide sensitivity. Expanding on these findings, we will leverage our group's laboratory and clinical expertise to 1) investigate the role of GR isoforms in resistance to enzalutamide, 2) define the broader effects of BET inhibition across a range of preclinical models of prostate cancer, and 3) investigate the activity of a novel BET inhibitor in men with metastatic CRPC whose disease has progressed on enzalutamide or abiraterone acetate.

项目摘要/摘要 雄激素受体（AR）指导的enzalutamide和Abiraterone乙酸酯是标准的一线 治疗转移性cast割前列腺癌（CRPC）患者的治疗方法。这些 药物通常具有良好的耐受性和有效的范围，可延迟疾病进展，延长生存和 改善生活质量，但两种药物的有效持续时间有限。难治性疾病的患者 通常对随后的AR靶向剂的响应不佳，目前没有预测性 有助于选择二线治疗的生物标志物。我们的小组和其他人确定了上调 糖皮质激素受体（GR）的一种对乙酸酯和乙酸阿比罗酮的抗性的机制。 我们的发现表明1）GR可能是一个可以预测患者是否会反应的生物标志物 enzalutamide或abiraterone以及2）阻止enzalutamide-和abiraterone的GR上调 患者可能导致肿瘤反应。在初步数据中，我们显示了具有可变n-的GR的同工型 末端可以在转移性CRPC中表达 促进enzalutamide耐药性，在某些患者衍生的器官培养物中可检测到。这将是 表征GRαC和其他GR同工型所必需的，以发展为生物标志物和A 治疗靶标。使用enzalutamide抗性的实验室模型，我们还发现GR 表达是表观遗传调节的，并用蛋白质的抑制剂进行治疗 抑制GR表达并恢复乙酸酯的敏感性。扩大这些发现，我们将 利用我们小组的实验室和临床专业知识1）研究GR同工型在抵抗中的作用 Enzalutamide，2）在一系列前列腺模型中定义BET抑制的更广泛效果 癌症和3）研究一种新型BET抑制剂在转移性CRPC男性的活性 已在恩扎拉胺或乙酸阿比罗酮上进展。