Role of oncogenic phosphorylated MED1 in aggressive prostate cancer

项目摘要/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)标志着该病的致命进展。慢性前列腺癌的现代治疗 使用肿瘤内和肾上腺雄激素合成的抑制剂(如醋酸阿比特龙)或更有效 雄激素受体(AR)拮抗剂(如苯扎鲁胺)。然而，这些代理只提供临时的 反应和存活率的小幅增加表明了抗药性的快速演变。除CRPC外，还有一个 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迅速的致命性。重要的是，随着醋酸阿比特龙的广泛使用 和苯扎鲁胺时，SCNC的出现频率较高。目前，还没有标准 对SCNC有效的治疗。从而了解CRPC/SCNC演变的发病机制 开发新的靶向疗法仍然是当务之急。此外，预测性和预见性 能够帮助“个人化”治疗和提高临床试验精确度的生物标志物是必要的。在……里面 初步研究发现，AKT诱导转录辅活化子异常磷酸化 UBE2C癌基因的表达和CRPC和/或SCNC细胞的生长需要介体1(MED1) 体外和体内。此外，药物抑制AKT可降低UBE2C癌基因的表达和 细胞在体外以磷酸化的MED1(p-MED1)特异性的方式生长。重要的是，p-的表达 当前列腺癌进展到CRPC和SCNC时，MED1显著增加。这些发现 支持我们的假设，即AKT诱导的异常MED1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)划定 CRPC/SCNC中p-MED1与染色质结合的基因组机制及整体基因调控； 确定AKT-p-MED1转录调控的生物学影响和临床相关性 CRPC/SCNC。这些目标的成功实现将显著影响对关键问题的理解 P-MED1在CRPC和SCNC中的致癌作用，为：(A)开发新的治疗方法奠定了基础 靶向AKT-p-MED1转录轴，(B)使用p-MED1作为选择AKT抑制剂的标记- 对“精确医学”临床试验敏感的患者，以及(C)确定新的预测性和预后 CRPC和SCNC的生物标志物。

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.