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

基本信息

批准号：
7826665
负责人：
WAEL EL-RIFAI
金额：
$ 31.93万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/7826665
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 Regimen Reporting Research Roche brand of trastuzumab Role Sampling Signal Pathway Stomach Survival Rate TP53 gene Testing Therapeutic Tissue Microarray 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

项目摘要

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）：我们和其他人描述了几种肿瘤中20q染色体基因的扩增和过表达。我们最近表明，该区域在大多数胃肠道腺癌（UGC；胃和食道）中被放大，并鉴定出Aurora激酶A（AURKA）是一种癌细胞促卵巢蛋白，该蛋白位于20 Q13染色体中。美国大约80％的患者出现了区域或远处转移。不幸的是，UGC的死亡率接近发病率，这表明可用的临床管理选择有限且通常无效。我们的研究表明，在我们测试的超过一半的肿瘤中，Aurka过表达。我们已经证明，Aurka通过抑制p53-和TAP73依赖性细胞凋亡来保护癌细胞免受药物诱导的凋亡。根据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，从而为癌细胞提供了有效的生存优势。在此提案中，我们计划研究Aurka在UGC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调节UGC中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作用。我们已经表明，Aurka蛋白调节了几种关键信号通路。 Aurka抑制剂可以代表一种新型有效的UGC患者，这些患者可以改善与该疾病化学疗法相关的当前反应和存活率。我们使用Aurka shrna敲低和小分子特异性抑制剂（MLN8054）的结果显示出令人鼓舞的体外和体内结果（初步数据）。我们将单独测试Aurka ShRNA敲低或抑制（MLN8054），还是与现有的化学治疗剂结合使用，可以使用异种移植肿瘤动物模型来增强体内治疗反应。在第三个目标中，我们将研究Aurka在UGC中的临床价值。我们计划分析UGC中Aurka编码序列中SNP的mRNA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。此外，将进行免疫组织化学分析，以评估包含600多个注释的UGC样品的组织微阵列上的Aurka，p53和Tap73的蛋白质表达。将进行统计分析，以确定与分子靶标，组织病理学和临床信息的显着关联。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，这些信息可能会对胃和食道腺癌患者的临床管理产生重大影响。公共卫生相关性：我们最近将Aurora激酶A（Aurka）的过表达表征为上胃肠道腺癌的共同分子靶标。在此提案中，我们计划表征Aurka在上胃肠道肿瘤发生中的作用，以识别其生物学，诊断，预后和治疗值。