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.

项目总结/文摘