Aurora Kinases as Therapeutic Targets in Pancreatic Cancer

描述(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，以及对晚期疾病患者缺乏有效的治疗。在我们之前的资助期间，我们确定并验证了Aurora A和Aurora B激酶作为治疗胰腺癌的药物靶点。我们还开发了一系列极光激酶抑制剂(Akis)，在临床前胰腺癌模型中显示出强大的活性。这些抑制剂被授权给一家生物技术公司，一种优化的先导药物(名为MP529)将于今年秋天进入临床试验。在R01的这次更新中，我们现在提议将我们的AKI工作提升到一个新的水平。到目前为止，一些早期极光酶抑制剂的I期临床试验结果表明，患者对极光酶抑制剂的反应率充其量可能是适度的。根据其他激酶靶向治疗的经验，我们假设癌细胞中存在决定其对Akis敏感性的基因改变(易损性背景)。通过识别这种脆弱性的背景，我们将能够开发新的生物标记物，用于选择AKI疗法的患者群体，或者开发新的基于AKI的联合疗法，以提高患者的反应。在这项建议中，我们寻求：a)确定患者肿瘤中会使肿瘤对Akis更敏感的基因变化，因为这样我们就可以只识别和治疗那些将从Akis中受益的患者，例如具有对Akis反应的生物标记物；b)验证二级靶点，当抑制这些二级靶点时，将增加癌细胞对Akis治疗的敏感性；以及c)开发新的药物来击中这些二级靶点，使患者的肿瘤对Akis敏感。这项建议的具体目标如下： 目的1：鉴定和验证胰腺癌细胞中的基因，当这些基因缺失或表达被抑制时，会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。 目的：通过比较基因组杂交(CGH)和组织芯片(TMA)对直接取自患者的胰腺肿瘤组织进行拷贝数和蛋白质表达分析，验证AIM 1中确定的基因靶点的临床相关性。 目的3：寻找抑制或敲除AIMS 1和AIMS 2中确定的基因的药物，并在临床前模型中评价其与Akis联合的抗癌活性。 这项建议工作应该有助于优化前景看好的极光激酶抑制剂在胰腺癌患者治疗中的应用。胰腺癌是美国癌症死亡的第四大病程。每年，美国约有3.7万人被发现患有胰腺癌，超过3.3万名患者将死于这种疾病。目前的提案旨在确定预测患者对极光酶抑制剂的反应的潜在生物标志物，并开发新型抗癌药物，使胰腺癌患者的肿瘤对极光酶抑制剂的治疗敏感。因此，该项目产生的结果有可能直接惠及胰腺癌患者，改善治疗，并降低医疗费用，使普通公众受益。

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.