The Role of Pim Kinases as a Novel Molecular Target in Pancreatic Cancer

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大常见原因。由于胰腺癌的侵袭性和缺乏早期发现的生物标志物，胰腺癌的发病率和死亡率几乎相同。K-RAS癌基因突变在90%的人胰腺导管腺癌(PDAC)中的存在强烈表明该基因突变在该疾病的发生发展中起着关键作用。然而，尽管进行了多年的研究，目前还没有成功应用于临床的抗RAS疗法。微阵列研究发现，与正常胰腺相比，胰腺癌组织/细胞中存在数百个差异表达基因。在永生化的人胰腺导管上皮细胞中，已发现致癌K-RAS激活后过度表达的基因之一是Pim-1激酶。最近，Pim家族的另一成员Pim-3激酶被发现异常表达，并在PDAC细胞系和患者肿瘤中阻断细胞凋亡。随着这些和其他观察结果表明Pim激酶是癌基因和凋亡抑制物，我们研究的总体目标是确定Pim激酶家族在PDAC生长中的功能意义。我们推测，抑制Pim功能将是对抗胰腺癌异常生长的有效途径。首先，我们将确定上调的Pim激酶基因在K-RAS介导的胰腺癌细胞系转化中的作用(特定目标1)。为了了解PIM激酶促进PDAC生长的机制(S)，识别PIM下游的新分子靶点将是有用的。最近，一个RUNX转录因子被发现是Pim-1的底物。我们计划确定RUNX转录因子是否是胰腺癌中Pim激酶的重要下游靶点(特异性目标2)。这项研究的结果将有助于确定K-RAS激活在Pim上调中的作用，并确定Pim抑制对PDAC生长的影响。此外，这些发现将使我们能够批判性地验证这些激酶作为PDAC治疗的新治疗靶点。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most common cause of cancer deaths in the United States. Due to the aggressive nature of this cancer and the lack of biomarkers for early detection, the incidence and mortality rates for pancreatic cancer are nearly equivalent. The presence of oncogenically mutated K-Ras in 90% of human pancreatic ductal adenocarcinomas (PDAC) strongly suggests a critical role for this genetic mutation in the development of this disease. However, despite many years of research, there are no anti-Ras therapies that have successfully reached the clinic. Microarray studies have revealed hundreds of genes that are differentially expressed in pancreatic cancer tissues/cells compared with the normal pancreas. One of the genes that have been found to be over-expressed after oncogenic K-Ras activation in immortalized human pancreatic ductal epithelial cells is the Pim-1 kinase. Most recently, another member of the Pim family, Pim-3 kinase, was shown to be aberrantly expressed and to block apoptosis in PDAC cell lines and patient tumors. With these and other observations implicating Pim kinases as oncogenes and inhibitors of apoptosis, the overall goal of our research is to determine the functional significance of the Pim kinase family in PDAC growth. We hypothesize that inhibition of Pim function will be an effective approach for antagonizing the aberrant growth of pancreatic carcinoma. Initially, we will determine the contribution of up- regulated Pim kinase genes in K-Ras mediated transformation of pancreatic cancer cell lines (specific aim 1). In order to understand the mechanism(s) by which Pim kinases promote PDAC growth, it will be instrumental to identify novel molecular targets downstream of the Pims. Recently, one of the RUNX transcription factors was found to be a substrate for Pim-1. We plan to determine whether the RUNX transcription factors are important downstream targets of Pim kinases in pancreatic cancer (specific aim 2). Results from the proposed study will help to define the role of K-Ras activation in Pim up-regulation and determine the consequences of Pim inhibition on PDAC growth. Furthermore, these findings will allow us to critically validate these kinases as novel therapeutic targets for PDAC treatment.