The role of Aurora Kinase A in Upper Gastrointestinal Adenocarcinomas

项目总结/摘要 我们和其他人已经描述了染色体20 q处基因的扩增和过表达， 几个肿瘤我们最近的研究表明，在大多数上消化道肿瘤中， 腺癌（UGC;胃和食管），并确定极光激酶A（AURKA）为癌细胞 位于染色体20 q13的促生存蛋白。在美国，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项是有限的，往往是无效的。我们的研究 在我们检测的一半以上的肿瘤中，AURKA过度表达。我们已经证明 AURKA通过抑制p53-和TAp 73-， 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- 通过抑制TAp 73的表达为癌细胞提供了有效的存活优势。 依赖性凋亡在这项提案中，我们计划研究分子，生物学和治疗方法。 AURKA在UGC中的潜力。在第一个目标中，我们计划确定AURKA在调节TAp 73中的作用。 依赖性凋亡我们将研究AURKA表达和敲低对TAp 73的影响。 依赖性凋亡我们还将确定AURKA对TAp 73转录活性的影响， 确定AURKA调节UGC中TAp 73的机制。第二个目标，我们将 研究体内AURKA抑制的生物学和分子学效应。我们已经证明 AURKA蛋白调节几个关键的信号通路。AURKA抑制剂可以代表一种新的， UGC患者的有效治疗，可改善与UGC相关的当前缓解率和生存率 化疗治疗这种疾病。我们的结果使用AURKA shRNA敲低和小分子特异性 AURKA抑制剂（MLN 8054）在体外和体内显示出有希望结果（初步数据）。我们将测试 无论是单独的AURKA shRNA敲低或抑制（MLN 8054）还是与现有的 使用异种移植肿瘤动物模型，化学治疗剂可以增强体内治疗反应。在 第三，探讨AURKA在UGC中的临床应用价值。我们计划分析mRNA 表达、DNA扩增和UGC中AURKA编码序列中SNP的单倍型。 我们还将分析AURKA和TAp 73促凋亡转录靶点的mRNA表达。在 此外，将进行免疫组织化学分析以评估AURKA，p53， 和TAp 73在包含600多个注释的UGC样品的组织微阵列上。统计分析将 以确定与分子靶点、组织病理学和临床 信息.我们希望完成这项提案将提供重要的临床，分子， 可能对患者的临床管理产生重大影响的病理生物学信息 胃和食道的腺癌。

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.