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.

项目概要/摘要 我们和其他人已经描述了染色体 20q 基因的扩增和过度表达 几个肿瘤。我们最近表明，该区域在大多数上消化道中被放大 腺癌（UGC；胃和食道）并确定极光激酶 A (AURKA) 为癌细胞 促生存蛋白，位于染色体 20q13。美国大约80%的患者 存在区域或远处转移。不幸的是，UGC 的死亡率接近发病率 率，表明可用的临床管理选择有限且往往无效。我们的研究 证明 AURKA 在我们测试的一半以上的肿瘤中过度表达。我们已经证明了 AURKA 通过抑制 p53- 和 TAp73- 来保护癌细胞免受药物诱导的细胞凋亡 依赖性细胞凋亡。根据我们最初的发现和初步数据，我们假设 AURKA 过度 通过抑制 TAp73- 的表达为癌细胞提供了强大的生存优势 依赖性细胞凋亡。在本提案中，我们计划研究分子、生物学和治疗学 AURKA 在 UGC 中的潜力。第一个目标是确定 AURKA 在调节 TAp73 中的作用- 依赖性细胞凋亡。我们将研究 AURKA 表达和敲低对 TAp73- 的影响 依赖性细胞凋亡。我们还将确定 AURKA 对 TAp73 转录活性的影响和 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 AURKA 抑制的生物学和分子效应。我们已经证明 AURKA 蛋白调节多个关键信号通路。 AURKA 抑制剂可以代表一种新颖且 对 UGC 患者进行有效治疗，可改善当前的反应和生存率 针对这种疾病的化疗。我们使用 AURKA shRNA 敲低和小分子特异性获得的结果 AURKA 抑制剂 (MLN8054) 在体外和体内均显示出有希望的结果（初步数据）。我们将测试 无论是 AURKA shRNA 敲低或抑制 (MLN8054) 单独使用还是与现有的组合使用 使用异种移植肿瘤动物模型，化疗药物可以增强体内治疗反应。在 第三个目标，我们将研究 AURKA 在 UGC 中的临床价值。我们计划分析 mRNA UGC 中 AURKA 编码序列中 SNP 的表达、DNA 扩增和单倍型。 我们还将分析 AURKA 和 TAp73 促凋亡转录靶标的 mRNA 表达。在 此外，还将进行免疫组织化学分析来评估AURKA、p53、 和 TAp73 在包含 600 多个带注释的 UGC 样本的组织微阵列上。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对患者的临床管理产生重大影响 胃和食道的腺癌。