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: 8453440
• 负责人: WAEL EL-RIFAI
• 金额: $ 29.52万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453440
• 关键词: 20q; 20q13; Adenocarcinoma; Animal Model; Apoptosis; Apoptotic; Area; Automobile Driving; Biological; Cancer Etiology; Cell Death; Cell Survival; Cellular biology; Cessation of life; Chromosomes; Clinical; Clinical Management; Code; Combined Modality Therapy; Consensus; Country; DNA amplification; Data; Diagnostic; Disease; Distant Metastasis; Esophageal Adenocarcinoma; Esophagus; Gastric Adenocarcinoma; Gene Targeting; Genes; Genetic Transcription; Gleevec; Haplotypes; Health; In Vitro; Incidence; Letters; Malignant Neoplasms; Molecular; Molecular Biology; Molecular Genetics; Molecular Target; Mutation; Outcome; Patients; Pharmaceutical Preparations; Proteins; Publications; Regimen; Reporting; Research; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Stomach; Survival Rate; Testing; Therapeutic; Tissue Microarray; United States; Upper digestive tract structure; Work; abstracting; aurora-A kinase; base; cancer cell; chemotherapy; effective therapy; gastrointestinal; improved; in vivo; inhibitor/antagonist; mRNA Expression; mortality; novel; oncogene addiction; overexpression; prognostic; protein expression; response; small hairpin RNA; small molecule; stem; stomach cardia; tumor; tumor xenograft; tumorigenesis

Project Summary/Abstract We and others have described amplification and overexpression of genes at chromosome 20q in several tumors. We have recently shown that this region is amplified in majority of upper gastrointestinal adenocarcinomas (UGCs; stomach and esophagus) and identified Aurora kinase A (AURKA) as a cancer cell pro-survival protein that is located in chromosome 20q13. 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 clinical management options are limited and often ineffective. Our studies demonstrate overexpression of AURKA in more than half of the tumors that we tested. We have demonstrated that AURKA protects cancer cells from drug-induced apoptosis through inhibiting both p53- and TAp73- dependent apoptosis. Based on our original findings and preliminary data, we hypothesize that AURKA over- expression provides cancer cells with a potent survival advantage through inhibition of TAp73- dependent apoptosis. In this proposal, we plan to investigate the molecular, biological, and therapeutic potential of AURKA in UGCs. In the first aim, we plan to determine the role of AURKA in regulating TAp73- dependent apoptosis. We will investigate the effects of AURKA expression and knockdown on TAp73- dependent apoptosis. We will also determine the effects of AURKA on TAp73 transcription activity and determine the mechanism(s) by which AURKA regulates TAp73 in UGCs. In the second aim, we will investigate the biological and molecular effects of AURKA inhibition in vivo. We have shown that AURKA protein regulates several critical signaling pathways. AURKA inhibitors can represent a novel and effective treatment for patients with UGCs that improve the current response and survival rates associated with chemotherapy for this disease. Our results using AURKA shRNA knockdown and small molecule specific inhibitor of AURKA (MLN8054) have shown promising results in vitro and in vivo (preliminary data). We will test whether AURKA shRNA knockdown or inhibition (MLN8054) alone or in combination with the existing chemotherapeutics can boost the therapeutic response in vivo using the xenografted tumors animal model. In the third aim, we will investigate the clinical value of AURKA in UGCs. We plan to analyse the mRNA expression, DNA amplification, and the haplotypes of the SNPs in the coding sequence of AURKA in UGCs. We will also analyse the mRNA expression of AURKA and the TAp73 pro-apoptotic transcription targets. In addition, immunohistochemical analysis will be performed to evaluate the protein expression of AURKA, p53, and TAp73 on tissue microarrays that contain more than 600 annotated UGC samples. Statistical analysis will be performed to determine significant associations with molecular targets, histopathological, and clinical information. We expect that completion of this proposal will provide important clinical, molecular, and pathobiological information that can have significant impact on the clinical management of patients with adenocarcinomas of the stomach and esophagus.

项目摘要/摘要 我们和其他人描述了在20q染色体中的基因的扩增和过表达 几个肿瘤。我们最近表明，该区域在大多数胃肠道中被放大 腺癌（UGC；胃和食道），并将Aurora激酶A（Aurka）鉴定为癌细胞 位于2013年第20季染色体中的蛋白生存蛋白。美国约80％的患者 存在区域或远处转移。不幸的是，UGC的死亡率发生率 费率，表明可用的临床管理方案有限且常常无效。我们的研究 在我们测试的超过一半以上的肿瘤中证明了Aurka的过表达。我们已经证明了 Aurka通过抑制P53-和TAP73-保护癌细胞免受药物诱导的凋亡 依赖性凋亡。根据我们的原始发现和初步数据，我们假设Aurka过度 表达通过抑制TAP73-为癌细胞提供有效的生存优势 依赖性凋亡。在此提案中，我们计划研究分子，生物学和治疗 Aurka在UGC中的潜力。在第一个目标中，我们计划确定Aurka在调节TAP73-的作用 依赖性凋亡。我们将研究Aurka表达和敲低对TAP73-的影响 依赖性凋亡。我们还将确定Aurka对Tap73转录活动的影响和 确定Aurka在UGC中调节TAP73的机制。在第二个目标中，我们将 研究体内过敏抑制的生物学和分子作用。我们已经表明 Aurka蛋白调节几种关键信号通路。 Aurka抑制剂可以代表小说，并且 为改善与之相关的当前反应和生存率的UGC患者的有效治疗 该疾病的化学疗法。我们使用Aurka shRNA敲低和小分子特异性的结果 Aurka的抑制剂（MLN8054）在体外和体内显示出令人鼓舞的结果（初步数据）。我们将测试 单独的Aurka shRNA敲低还是抑制（MLN8054），还是与现有的 化学疗法可以使用异种移植肿瘤动物模型在体内增强治疗反应。在 第三目的是，我们将研究Aurka在UGC中的临床价值。我们计划分析mRNA UGC中Aurka的编码序列中SNP的表达，DNA扩增和单倍型。 我们还将分析Aurka的mRNA表达和TAP73促凋亡转录靶标。在 此外，还将进行免疫组织化学分析，以评估Aurka的蛋白质表达，p53， 和TAP73在包含600多个带注释的UGC样品的组织微阵列上。统计分析将 进行以确定与分子靶标，组织病理学和临床的显着关联 信息。我们预计该提案的完成将提供重要的临床，分子和 病理生物学信息可能会对患者的临床管理产生重大影响 胃和食道的腺癌。