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

Pim 激酶作为胰腺癌新分子靶点的作用

• 批准号: 7342230
• 负责人: Antonio Thomas Baines
• 金额: $ 9.29万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342230
• 关键词: Adenocarcinoma Cell; Apoptosis; Apoptosis Inhibitor; Binding; Biological Markers; Cancer Etiology; Cancer cell line; Cell Line; Cells; Cessation of life; Clinic; Development; Disease; Ductal Epithelial Cell; Early Diagnosis; Family; Foundations; Gene Expression; Gene Mutation; Genes; Genome; Goals; Growth; Growth and Development function; Human; Incidence; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular Target; Mutate; Nature; Oncogene Proteins; Oncogenes; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic carcinoma; Patients; Phosphotransferases; Pilot Projects; Protein-Serine-Threonine Kinases; Ras Inhibitor; Ras Signaling Pathway; Rate; Research; Role; Sampling; Signal Transduction; Testing; Therapeutic Intervention; Tissues; Transcriptional Activation; United States; Up-Regulation; cancer therapy; member; mortality; novel; novel therapeutics; proto-oncogene protein pim; proto-oncogene protein pim-1; therapeutic target; transcription factor; tumor

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.

描述（由申请人提供）：胰腺癌是美国第四大最常见的癌症死亡原因。由于这种癌症的侵袭性以及缺乏早期检测的生物标志物，胰腺癌的发病率和死亡率几乎相同。 90% 的人类胰腺导管腺癌 (PDAC) 中存在致癌突变的 K-Ras，强烈表明这种基因突变在这种疾病的发展中发挥着关键作用。然而，尽管经过多年的研究，仍然没有抗Ras疗法成功进入临床。微阵列研究揭示了数百个基因在胰腺癌组织/细胞中与正常胰腺相比存在差异表达。 Pim-1 激酶是在永生化人胰腺导管上皮细胞中致癌 K-Ras 激活后发现过度表达的基因之一。最近，Pim 家族的另一个成员 Pim-3 激酶被证明在 PDAC 细胞系和患者肿瘤中异常表达并阻止细胞凋亡。这些和其他观察表明 Pim 激酶是癌基因和细胞凋亡抑制剂，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方法。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贡献（具体目标 1）。为了了解 Pim 激酶促进 PDAC 生长的机制，识别 Pim 下游的新分子靶标将很有帮助。最近，发现其中一种 RUNX 转录因子是 Pim-1 的底物。我们计划确定 RUNX 转录因子是否是胰腺癌中 Pim 激酶的重要下游靶标（具体目标 2）。拟议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严格验证这些激酶作为 PDAC 治疗的新治疗靶点。