Role of oncogenic phosphorylated MED1 in aggressive prostate cancer

致癌磷酸化 MED1 在侵袭性前列腺癌中的作用

• 批准号: 9383505
• 负责人: STEVEN K CLINTON
• 金额: $ 5.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383505
• 关键词: AKT inhibition; Acetates; Adenocarcinoma; Adrenal Glands; Androgen Receptor; Androgens; Binding; Biological; Biopsy Specimen; Castration; Chromatin; Clinical; Clinical Trials; Correlation Studies; DNA; Development; Disease Progression; Dreams; Evolution; Exonuclease; Foundations; Frequencies; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genomics; Growth; Human; Immunohistochemistry; In Vitro; Incidence; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Metastatic Prostate Cancer; Molecular; Neuroendocrine Carcinoma; Neuroendocrine Cell; Oncogene Activation; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathologist; Patients; Pharmacology; Phase; Phosphorylation; Prognostic Marker; Prostate Adenocarcinoma; Proto-Oncogene Proteins c-akt; Research; Resistance; Role; Sampling; Technology; Transcription Coactivator; Transcriptional Regulation; abiraterone; androgen sensitive; cell growth; chromatin immunoprecipitation; clinically relevant; experience; hormone therapy; improved; in vivo; inhibitor/antagonist; new therapeutic target; novel; novel marker; novel therapeutics; personalized medicine; precision medicine clinical trials; predictive marker; programs; prostate cancer cell; response; transcription factor; transcriptome; tumor; tumorigenesis

Project Summary/Abstract The evolution of prostate cancer from an androgen-dependent state (ADPC) to castration-resistant adenocarcinoma (CRPC) marks the lethal progression of the disease. Contemporary therapy for CRPC employs inhibitors of intra-tumoral and adrenal androgen synthesis (e.g. abiraterone acetate) or more potent androgen receptor (AR) antagonists (e.g. enzalutamide). However, these agents only provide a temporary response and modest increase in survival indicating a rapid evolution of resistance. In addition to CRPC, a significant number of patients develop small cell neuroendocrine carcinoma (SCNC) after hormonal therapy. SCNC is extremely aggressive and rapidly fatal. Importantly, with the widespread use of abiraterone acetate and enzalutamide, a greater frequency of the SCNC has been observed. Currently, there is no standard therapy that is effective for SCNC. Thus understanding the pathogenesis of CRPC/SCNC evolution and development of novel targeted therapies remain urgent needs. In addition, predictive and prognostic biomarkers that can help “personalize” therapy and improve the precision of clinical trials are necessary. In preliminary studies, we have found that AKT-induced aberrant phosphorylation of transcription coactivator Mediator 1 (MED1) is required for UBE2C oncogene expression and for growth of CRPC and/or SCNC cells in vitro and in vivo. Furthermore, pharmacological AKT inhibition decreases UBE2C oncogene expression and cell growth in vitro in a phosphorylated MED1 (p-MED1)-specific manner. Importantly, the expression of p- MED1 significantly increases when human prostate cancer progresses to CRPC and SCNC. These findings support our hypothesis that AKT-induced aberrant MED1 phosphorylation drives an oncogenic gene expression program for CRPC/SCNC growth and progression. Our specific aims are to: (1) delineate the genomic mechanisms of p-MED1 binding to chromatin and global gene regulation in CRPC/SCNC; and (2) determine the biological impact and clinical relevance of AKT-p-MED1 transcriptional regulation in CRPC/SCNC. The successful completion of these aims will significantly impact the understanding of the critical oncogenic role of p-MED1 in CRPC and SCNC, laying the foundation for: (a) developing new therapies targeting the AKT-p-MED1 transcription axis, (b) employing p-MED1 as a marker for selecting AKT inhibitor- sensitive patients for “precision medicine” clinical trials, and (c) identifying new predictive and prognostic biomarkers for CRPC and SCNC.

项目总结/摘要 前列腺癌从雄激素依赖状态（ADPC）到去势抵抗的演变 腺癌（CRPC）标志着疾病的致命进展。CRPC的现代治疗 使用肿瘤内和肾上腺雄激素合成的抑制剂（例如醋酸阿比特龙）或更有效的 雄激素受体（AR）拮抗剂（例如恩杂鲁胺）。然而，这些代理商仅提供临时的 反应和适度增加的生存表明快速演变的阻力。除CRPC外， 大量患者在激素治疗后发展为小细胞神经内分泌癌（SCNC）。 SCNC具有极强的攻击性和快速致命性。重要的是，随着醋酸阿比特龙的广泛使用， 和恩杂鲁胺时，观察到SCNC的发生率更高。目前，没有标准 对SCNC有效的治疗。从而了解CRPC/SCNC演变的发病机制， 开发新的靶向治疗仍然是迫切的需求。此外，预测和预后 生物标记物，可以帮助“个性化”治疗和提高临床试验的精度是必要的。在 初步研究发现，AKT诱导的转录辅激活因子的异常磷酸化， 介体1（MED 1）是UBE 2C癌基因表达和CRPC和/或SCNC细胞在大肠杆菌中生长所必需的。 体外和体内。此外，药理学AKT抑制降低了UBE 2C癌基因表达， 以磷酸化MED 1（p-MED 1）特异性方式体外细胞生长。重要的是，表达的p- 当人前列腺癌进展为CRPC和SCNC时，MED 1显著增加。这些发现 支持我们的假设，AKT诱导的异常MED 1磷酸化驱动致癌基因 CRPC/SCNC生长和进展的表达程序。我们的具体目标是：（1）界定 CRPC/SCNC中p-MED 1与染色质结合和全局基因调控的基因组机制;和（2） 确定AKT-p-MED 1转录调控在人乳腺癌中的生物学影响和临床相关性。 CRPC/SCNC。这些目标的成功实现将极大地影响对关键问题的理解。 p-MED 1在CRPC和SCNC中的致癌作用，为以下方面奠定了基础：（a）开发新疗法 靶向AKT-p-MED 1转录轴，（B）使用p-MED 1作为用于选择AKT抑制剂的标记物， 用于“精准医学”临床试验的敏感患者，以及（c）确定新的预测和预后 CRPC和SCNC的生物标志物。