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: 10194407
• 负责人: STEVEN K CLINTON
• 金额: $ 41.37万
• 依托单位: DUKE 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194407
• 关键词: AKT inhibition; Acetates; Adenocarcinoma; Adrenal Glands; Androgen Receptor; Androgens; Binding; Biological; Biopsy Specimen; Cancer Cell Growth; 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.

项目概要/摘要 前列腺癌从雄激素依赖状态（ADPC）到去势抵抗状态的演变 腺癌 (CRPC) 标志着 CRPC 的现代治疗的致命进展。 采用肿瘤内和肾上腺雄激素合成抑制剂（例如醋酸阿比特龙）或更有效的抑制剂 雄激素受体（AR）拮抗剂（例如恩杂鲁胺）然而，这些药物只能提供暂时的作用。 反应和存活率的适度增加表明耐药性的快速演变。 大量患者在激素治疗后发展为小细胞神经内分泌癌（SCNC）。 重要的是，随着醋酸阿比特龙的广泛使用，SCNC 具有极强的侵袭性并可迅速致命。 和恩杂鲁胺，已观察到 SCNC 发生率较高，目前尚无标准。 对 SCNC 有效的治疗，从而了解 CRPC/SCNC 演变的发病机制和 此外，预测和预后仍迫切需要开发新型靶向疗法。 可以帮助“个性化”治疗并提高临床试验精度的生物标志物是必要的。 初步研究，我们发现AKT诱导转录辅激活因子异常磷酸化 介质 1 (MED1) 是 UBE2C 癌基因表达以及 CRPC 和/或 SCNC 细胞生长所必需的 此外，药理学 AKT 抑制可降低 UBE2C 癌基因的表达和 细胞以磷酸化 MED1 (p-MED1) 特异性方式在体外生长，重要的是，p- 的表达。 当人类前列腺癌进展为 CRPC 和 SCNC 时，MED1 显着增加。 支持我们的假设：AKT 诱导的异常 MED1 磷酸化驱动致癌基因 我们的具体目标是：(1) 描绘 CRPC/SCNC 生长和进展的表达计划。 p-MED1 与染色质结合的基因组机制和 CRPC/SCNC 中的全局基因调控；以及 (2) 确定 AKT-p-MED1 转录调控的生物学影响和临床相关性 CRPC/SCNC 的成功完成将极大地影响对关键问题的理解。 p-MED1 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-MED1 转录轴，(b) 采用 p-MED1 作为选择 AKT 抑制剂的标记- 敏感患者进行“精准医学”临床试验，以及（c）确定新的预测和预后 CRPC 和 SCNC 的生物标志物。

项目成果

Erratum to "Pre-existing Castration-resistant Prostate Cancer-like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy" [Eur Urol 2022;81(5):446-55].

“原发性前列腺癌中预先存在的去势抵抗性前列腺癌样细胞促进对激素治疗的抵抗”的勘误 [Eur Urol 2022;81(5):446-55]。

• 发表时间: 2023-06
• 影响因子: 23.4
• 作者: Cheng, Qing;Butler, William;Zhou, Yinglu;Zhang, Hong;Tang, Lu;Perkinson, Kathryn;Chen, Xufeng;Jiang, Xiaoyin Sara;McCall, Shannon J;Inman, Brant A;Huang, Jiaoti
• 通讯作者: Huang, Jiaoti

The expanded role of fatty acid metabolism in cancer: new aspects and targets.

脂肪酸代谢在癌症中的扩大作用：新方面和目标。

• 发表时间: 2019-09
• 影响因子: 5.3
• 作者: Chen, Ming;Huang, Jiaoti
• 通讯作者: Huang, Jiaoti