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: 7742588
• 负责人: WAEL EL-RIFAI
• 金额: $ 31.45万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742588
• 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; Oncogenes; Outcome; Patients; Pharmaceutical Preparations; Proteins; Publications; Reporting; Research; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Stomach; Survival Rate; TP53 gene; Testing; Therapeutic; Tissue Microarray; Treatment Protocols; United States; Upper digestive tract structure; Work; addiction; aurora-A kinase; base; cancer cell; chemotherapy; effective therapy; gastrointestinal; improved; in vivo; inhibitor/antagonist; mRNA Expression; mortality; novel; overexpression; prognostic; protein expression; public health relevance; response; small hairpin RNA; small molecule; stem; stomach cardia; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): 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 analyze the mRNA expression, DNA amplification, and the haplotypes of the SNPs in the coding sequence of AURKA in UGCs. We will also analyze 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. PUBLIC HEALTH RELEVANCE: We have recently characterized overexpression of Aurora Kinase A (AURKA) as a common molecular target in upper gastrointestinal adenocarcinomas. In this proposal, we plan to characterize the role of AURKA in upper gastrointestinal tumorigenesis in order to identify its biological, diagnostic, prognostic, and therapeutic values.

描述（由申请人提供）：我们和其他人已经在几个肿瘤中描述了染色体20q上的基因扩增和过表达。我们最近发现，该区域在大多数上胃肠道腺癌（UGCs，胃和食道）中被扩增，并鉴定出极光激酶A （AURKA）是位于染色体20q13上的癌细胞促生存蛋白。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，这表明现有的临床管理选择有限，而且往往无效。我们的研究表明，在我们测试的一半以上的肿瘤中，AURKA过表达。我们已经证明AURKA通过抑制p53-和TAp73-依赖性的凋亡来保护癌细胞免受药物诱导的凋亡。基于我们的原始发现和初步数据，我们假设AURKA过表达通过抑制TAp73依赖性凋亡为癌细胞提供了强大的生存优势。在本研究中，我们计划研究AURKA在UGCs中的分子、生物学和治疗潜力。在第一个目标中，我们计划确定AURKA在调节tap73依赖性细胞凋亡中的作用。我们将研究AURKA表达和敲低对tap73依赖性细胞凋亡的影响。我们还将确定AURKA对TAp73转录活性的影响，并确定AURKA在UGCs中调控TAp73的机制。在第二个目标中，我们将研究AURKA抑制在体内的生物学和分子效应。我们已经证明AURKA蛋白调节了几个关键的信号通路。AURKA抑制剂可能是UGCs患者的一种新的有效治疗方法，可以改善与该疾病化疗相关的当前反应和生存率。我们使用AURKA shRNA敲除和AURKA小分子特异性抑制剂（MLN8054）的研究结果在体外和体内均显示出令人满意的结果（初步数据）。我们将在异种移植肿瘤动物模型中测试AURKA shRNA敲低或抑制（MLN8054）单独或与现有化疗药物联合使用是否可以提高体内治疗反应。在第三个目标中，我们将探讨AURKA在UGCs中的临床价值。我们计划分析UGCs中AURKA编码序列snp的mRNA表达、DNA扩增和单倍型。我们还将分析AURKA和TAp73促凋亡转录靶点的mRNA表达。此外，将进行免疫组织化学分析，以评估AURKA、p53和TAp73在包含600多个带注释的UGC样本的组织微阵列上的蛋白表达。将进行统计分析以确定与分子靶点、组织病理学和临床信息的显著关联。我们期望这项研究的完成将提供重要的临床、分子和病理生物学信息，对胃和食管癌患者的临床治疗产生重大影响。公共卫生相关性：我们最近发现极光激酶A （AURKA）的过表达是上消化道腺癌的一个常见分子靶点。在这项提议中，我们计划描述AURKA在上胃肠道肿瘤发生中的作用，以确定其生物学，诊断，预后和治疗价值。