Aurora Kinases as Therapeutic Targets in Pancreatic Cancer

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因。它也是所有恶性肿瘤中死亡率最高的。这是由于缺乏早期发现的方法，以及缺乏对晚期疾病患者的有效治疗。在我们之前的资助期间，我们确定并验证了Aurora A和Aurora B激酶作为胰腺癌的药物靶点。我们还开发了一系列极光激酶抑制剂（AKI），在临床前胰腺癌模型中显示出有效的活性。这些抑制剂被授权给一家生物技术公司，一种优化的铅（称为MP529）将于今年秋天进入临床试验。在R 01的更新中，我们现在建议将我们的阿基工作提升到一个新的水平。迄今为止，一些早期极光激酶抑制剂的I期临床试验结果表明，患者对极光激酶抑制剂的反应率最多可能是适度的。基于其他激酶靶向治疗的经验，我们假设癌细胞中存在遗传改变（脆弱性背景），决定了它们对AKI的敏感性。通过识别这种脆弱性的背景，我们将能够开发用于选择阿基治疗的患者人群的新生物标志物，或增加患者反应的基于阿基的新组合疗法。在该提议中，我们寻求：a）鉴定患者肿瘤中的遗传改变，其将使肿瘤对AKI更敏感，因为我们然后可以仅鉴定和治疗将受益于AKI的那些患者，例如具有对AKI响应的生物标志物; B）验证二级靶标，其在被抑制时将增加癌细胞对AKI治疗的敏感性; c）开发新的药物来打击这些次要靶点，使患者的肿瘤对AKI敏感。这项建议的具体目标如下： 目标1：以鉴定和验证胰腺癌细胞中的基因，所述基因在缺失或其表达被抑制时将导致胰腺癌细胞对极光激酶抑制剂的敏感性增加。这将使用高通量小干扰RNA（siRNA）来完成。 目标二：通过对直接取自患者的胰腺肿瘤组织进行基于拷贝数和蛋白质表达分析的比较基因组杂交（CGH）和组织微阵列（TMA），验证目标1中鉴定的基因靶的临床相关性。 目标3：鉴定抑制或敲除目标1和2中鉴定的基因的药剂，并在临床前模型中评价其与AKI组合的抗癌活性。 这项建议工作将有助于优化有前途的极光激酶抑制剂治疗胰腺癌患者的效用。胰腺癌是美国癌症死亡的第四大原因。每年，美国约有37，000人被发现患有胰腺癌，超过33，000名患者将死于这种疾病。目前的提案旨在确定潜在的生物标志物，预测患者对极光激酶抑制剂的反应，并开发新的抗癌药物，使胰腺癌患者的肿瘤对极光激酶抑制剂的治疗敏感。因此，该项目产生的结果有可能直接使胰腺癌患者受益，改善治疗，并降低公众的医疗费用。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related death in the United States. It also has the worst mortality rate of all malignancies. This is due to the lack of a method for early detection and the lack of effective treatment for patients with advanced disease. During our previous grant period, we identified and validated Aurora A and Aurora B kinases as drug targets in pancreatic cancer. We also developed a series of aurora kinase inhibitors (AKIs) that showed potent activities in preclinical pancreatic cancer models. The inhibitors were licensed to a biotech company and an optimized lead (called MP529) will enter clinical trials this fall. In this renewal of our R01 we are now proposing to take our AKI work to the next level. Phase I clinical trial results from some early aurora kinase inhibitors have so far indicated that patient response rates to aurora kinase inhibitors might be modest at best. Based on the experience with other kinase targeted therapies, we hypothesize that there exist genetic alterations (contexts of vulnerability) in cancer cells that dictate their sensitivity to AKIs. By identifying such contexts of vulnerability we will be able to develop either new biomarkers for selecting patient populations for AKI therapies or new AKI based combination therapies that increase patient response. In this proposal, we seek to: a) identify the genetic alterations in patients' tumors which would make the tumors more sensitive to AKIs because we could then identify and treat only those patients who would benefit from AKIs, e.g. have biomarker for response to AKIs; b) validate secondary targets which, when inhibited, will increase the sensitivity of cancer cells to treatment with AKIs and; c) develop new agents to hit those secondary targets to sensitize patients' tumors to AKIs. The specific aims of this proposal are as follow: Aim 1: to identify and validate genes in pancreatic cancer cells which, when deleted or when their expression is inhibited will lead to increased sensitivity of pancreatic cancer cells to aurora kinase inhibitors. This will be done using high throughput small interfering RNA (siRNA). Aim 2: to validate the clinical relevance of the gene targets identified in Aim 1 by comparative genomics hybridization (CGH) and tissue microarray (TMA) based copy number and protein expression analyses of pancreatic tumor tissues taken directly from patients. Aim 3: to identify agents that suppress or knock out genes identified in Aims 1 and 2 and evaluate their anti-cancer activity in combination with AKIs in preclinical models. This proposal work should help optimize the utility of promising aurora kinase inhibitor for the treatment of patients with pancreatic cancer. Pancreatic cancer is the fourth leading course of cancer death in the United States. Every year, about 37,000 people in the United States will be found to have pancreatic cancer and over 33,000 patients will die of the disease. The current proposal seeks to identify potential biomarkers that would predict patients' response to aurora kinase inhibitors and to develop novel anti-cancer agents that would sensitize pancreatic cancer patients' tumor to the treatment of aurora kinase inhibitors. The results generated from this project therefore have the potential to directly benefit pancreatic cancer patients with improved treatment and the general public with reduced healthcare cost.