Aurora Kinase as a Therapeutic Target in Cancer

简介(申请人提供)：胰腺癌位居第四位 美国死于癌症的原因。它的存活率是最差的 在S.E.E.R.数据库中追踪到的任何恶性肿瘤。新目标的发现 在胰腺癌细胞中的存在是至关重要的，对于 预防和治疗胰腺癌。在这项提案中，我们 描述一个新的靶标极光激酶，它是染色体分离的关键调节因子 存在于胰腺癌细胞中，通过额外的研究，我们认为可以 用于为患有这种疾病的患者开发新的治疗方法。极光激酶是 丝氨酸/苏氨酸激酶超家族的成员。他们正在转型 容量(是癌基因)，存在于多种人类肿瘤中 (尤其是胰腺癌)。在初步工作中，我们已经记录了 Aurora激酶在所有胰腺癌细胞系中表达上调，但在 正常胰腺导管细胞。此外，它在胰腺中表达上调。 癌症直接取自患者，在一些患者的体内也会被放大 肿瘤。这一初步信息使极光激酶成为一种非常有吸引力的新技术 胰腺癌的靶点。这项建议的具体目的是：1. 进一步验证极光激酶作为胰腺癌靶点的可行性。假说 极光激酶是胰腺癌患者的重要靶点 细胞。2.设计干扰极光激酶活性的药物。 这个假设是可以找到选择性地抑制 激活剂。将使用两种特殊技术来生成铅剂。一如既往 从提案中可以看出，我们有一个可以开始设计工作的线索。3.至 对与极光相互作用的试剂进行体外和体内测试 选择一种可能用于临床试验的试剂 晚期胰腺癌患者。假设是我们可以 发现可以抑制生长(或引起)的极光激酶抑制剂 胰腺癌细胞在体外和体内的作用)。极光激活剂 有相当大的潜力成为患者的非常重要的目标 胰腺癌，可以针对其设计新的治疗方法并 发展起来的。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of death from cancer in the United States. It has the worst survival of any malignancy followed in the S.E.E.R. database. The discovery of new targets present in pancreatic cancer cells is critically important, both for the prevention and for the treatment of pancreatic cancer. In this proposal, we describe a new target, aurora kinase, a key regulator of chromosome segregation present in pancreatic cancer cells which, with additional work, we feel can be used to develop new therapies for patients with the disease. Aurora kinases are members of the serine/threonine kinase superfamily. They have transforming capacities (are oncogenes) and are present in a variety of human tumors (particularly pancreatic cancer). In preliminary work, we have documented that aurora kinase is upregulated in all pancreatic cancer cell lines but not in normal pancreatic ductal cells. In addition, it is upregulated in pancreatic cancer taken directly from patients and is also amplified in some patients' tumors. This preliminary information makes aurora kinase a very attractive new target in pancreatic cancer. The specific aims of this proposal are: 1. To further validate aurora kinase as a target in pancreatic cancer. The hypothesis is that aurora kinase is an important target in patients' pancreatic cancer cells. 2. To design agents which interfere with the activity of aurora kinase. The hypothesis is that agents can be found which can selectively inhibit the kinase. Two special techniques will be used to generate lead agents. As will be seen in the proposal, we have a lead from which to begin our design work. 3. To perform in vitro and in vivo testing of agents which interact with aurora kinase to select an agent which would be a candidate for clinical trials in patients with advanced pancreatic cancer. The hypothesis is that we can discover inhibitors of aurora kinase which can inhibit growth (or cause apoptosis) of pancreatic cancer cells both in vitro and in vivo. Aurora kinase has considerable potential to be a very important target in patients' pancreatic cancers, against which new therapeutics can be designed and developed.