The role of Aurora Kinase A in Upper Gastrointestinal Adenocarcinomas

极光激酶 A 在上消化道腺癌中的作用

• 批准号: 8794913
• 负责人: WAEL EL-RIFAI
• 金额: $ 35.33万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794913
• 关键词: 20q; Adenocarcinoma; Apoptotic; Biological; Biology; Bypass; CCND1 gene; Cancer Etiology; Cell Death; Cell Survival; Cells; Cessation of life; Clinical Trials; Country; Data; Development; Diagnostic; Distant Metastasis; Esophageal; Esophageal Adenocarcinoma; Eukaryotic Initiation Factor-4E; Feedback; Funding; Genes; Health; Incidence; Institution; MAPK3 gene; Malignant Neoplasms; Measurable; Mediating; Medical; Messenger RNA; Molecular; Molecular Biology; Oncogenes; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt; Publications; Regulation; Reporting; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stomach; Therapeutic; Therapeutic Intervention; Translations; United States; Up-Regulation; Vascular Endothelial Growth Factors; Work; aurora-A kinase; base; cancer cell; clinically significant; gastroesophageal junction adenocarcinoma; gastrointestinal; human FRAP1 protein; improved; inhibitor/antagonist; mTOR Inhibitor; mortality; novel; overexpression; prognostic; protein expression; public health relevance; response; stem; stomach cardia; therapy resistant; tumor

DESCRIPTION (provided by applicant): Upper gastrointestinal adenocarcinomas (UGCs) of the esophagus and stomach are a major health problem world-wide. Approximately 80% of patients in the United States present with regional or distant metastases. Unfortunately, the mortality rates for UGCs approach incidence rates, suggesting that the available therapeutic options are limited and ineffective. Understanding the molecular biology and signaling networks of UGCs is a critical step in order to develop specific therapies that can potentially improve the outcomes. This proposal stems from our original finding that Aurora kinase A (AURKA) is a critical target at the 20q amplicon that is overexpressed in approximately 60% of UGCs. Our recent studies indicate that the AURKA protein is a potent pro-survival protein that promotes resistance to chemotherapeutic drugs through activation of oncogenic signaling pathways. Our preliminary data demonstrate that AURKA mediates up- regulation and phosphorylation of EIF4E. We have also shown that cells with acquired resistance to mTOR inhibitor RAD001 develop an increase in the protein level of AURKA, as compared to their parental cells, whereas overexpression of AURKA leads to resistance to mTOR inhibitor RAD001. Several recent studies have shown that EIF4E is a key component of cap-dependent translation of several oncogenes such as c- MYC, CCND1, and VEGF. We have uncovered the presence of a novel positive feedback loop of AURKA- EIF4E-MYC that drives cancer cell survival and resistance to therapy. In addition, our data provide evidence that AURKA can bypass key signaling pathways and phosphorylate EIF4E independent of mTOR, AKT and ERK1/2 activities. Based on our novel discoveries, we hypothesize that activation of the AURKA-EIF4E-MYC signaling loop and EIF4E-dependent oncogenic translation drive cancer cell survival as well as resistance to RAD001. In Aim 1, we will investigate the role of AURKA in regulating EIF4E cap-dependent translation in UGCs. We will investigate the mechanisms and molecular functions of the AURKA-EIF4E-MYC loop in Aim 2. Aim 3 of this proposal will determine the potential clinical significance of the AURKA-EIF4E-MYC axis. In this aim, we will also investigate the therapeutic potential of targeting the AURKA-EIF4E-MYC axis using AURKA inhibitor MLN8237 alone or in combinations for overcoming resistance to RAD001. Upon completion of our work, we expect to unveil a new paradigm for molecular mechanisms regulating cancer cell survival by AURKA-EIF4E-MYC axis. The translational components of this project have been established with measurable end points that could facilitate the development of better diagnostic, prognostic, and possibly therapeutic interventions. Therefore, our findings will have a positive impact on understanding the biology which could accelerate the development of novel medical treatments for the deadly UGCs.

描述（申请人提供）：食道和胃的上胃肠道腺癌（UGCs）是世界范围内的主要健康问题。在美国，大约80%的患者出现局部或远处转移。不幸的是，UGCs的死亡率接近发病率，这表明可用的治疗选择有限且无效。了解UGCs的分子生物学和信号网络是开发可能改善结果的特定治疗方法的关键一步。这一建议源于我们最初的发现，极光激酶A （AURKA）是20q扩增子的关键靶点，在大约60%的UGCs中过表达。我们最近的研究表明，AURKA蛋白是一种有效的促生存蛋白，通过激活致癌信号通路促进对化疗药物的耐药性。我们的初步数据表明，AURKA介导了EIF4E的上调和磷酸化。我们还发现，与亲本细胞相比，对mTOR抑制剂RAD001产生获得性抗性的细胞会增加AURKA蛋白水平，而AURKA的过表达会导致对mTOR抑制剂RAD001产生抗性。最近的几项研究表明，EIF4E是一些癌基因（如c- MYC、CCND1和VEGF）帽依赖翻译的关键成分。我们发现了AURKA- EIF4E-MYC的一个新的正反馈回路，它驱动癌细胞存活和对治疗的抵抗。此外，我们的数据提供了证据，证明AURKA可以绕过关键信号通路，独立于mTOR、AKT和ERK1/2活性磷酸化EIF4E。基于我们的新发现，我们假设AURKA-EIF4E-MYC信号回路的激活和eif4e依赖的致癌翻译驱动癌细胞存活以及对RAD001的抗性。在Aim 1中，我们将研究AURKA在调节UGCs中EIF4E帽依赖翻译中的作用。我们将在Aim 2中研究AURKA-EIF4E-MYC环的机制和分子功能。该提案的目标3将确定AURKA-EIF4E-MYC轴的潜在临床意义。为此，我们还将研究AURKA抑制剂MLN8237单独或联合靶向AURKA- eif4e - myc轴克服RAD001耐药的治疗潜力。在我们的工作完成后，我们期望揭开AURKA-EIF4E-MYC轴调节癌细胞存活的分子机制的新范式。这个项目的翻译部分已经建立了可测量的终点，可以促进更好的诊断、预后和可能的治疗干预措施的发展。因此，我们的发现将对了解生物学产生积极影响，这可能会加速开发针对致命UGCs的新型医学治疗方法。