P-1: Regulation of Pancreatic Cancer Cell Production and Survival by GSK-3B

胰腺癌是当今美国人面临的最致命的实体瘤。虽然第11位在 它在癌症死亡率中排名第五。因此，迫切需要了解分子 胰腺癌的潜在发展机制，希望这将导致预防性 和治疗策略来改善疾病的结果。虽然潜在的病因和 胰腺导管癌的病理生理学知之甚少，有越来越多的发表 这项工作和本申请中提出的初步数据表明，控制细胞的信号通路 增殖、分化和凋亡在胰腺癌中失调。机械论 该提案中概述的实验与胰腺癌100%相关，并将测试中枢神经系统。 GSK-3 $过表达促进胰腺癌细胞增殖和存活假说 因此是可行的治疗靶点。我们假设：（a）GSK-3 <$基因是在一个 （B）致癌性K-Ras信号传导调节胰腺癌患者亚群的表达; GSK-3启动子通过其对Ets-1、Ets-2和AP-1转录因子的作用;（c）c-Src是GSK-3启动子的调节因子， GSK-3蛋白过表达;（d）GSK-3是LSL-KRasG12 D中PDA发生所必需的。 胰腺癌小鼠模型;（e）恩扎鲁肽将在体内抑制GSK-3功能。 为了检验这些假设，我们将（1）确定调节 胰腺癌组织中GSK-30的表达(2)确定 GSK-3在胰腺癌发病机制中的作用(3)执行第二阶段 未治疗的转移性胰腺炎中的恩扎他林和吉西他滨的研究 适合活检的转移癌患者。总之，本报告中概述的研究 该提案将提供有关调节GSK-3表达的机制的宝贵信息， 胰腺癌、GSK-3在胰腺癌发展中的作用以及GSK-3抑制对胰腺癌的影响 胰腺癌的治疗此外，越来越多的证据表明GSK-3参与了 许多人类恶性肿瘤，因此，在本提案中进行的研究中获得的信息可能 促进我们对该激酶在其他人类肿瘤中的理解。

Pancreatic adenocarcinoma is the most lethal solid tumor challenging Americans today. Although 11th in prevalence, it ranks fifth in cancer mortality. Therefore, urgency is needed to understand the molecular mechanisms underlying the development of pancreatic cancer with the hope that this will lead to preventative and treatment strategies to improve the outcome of the disease. Although the underlying etiology and pathophysiology of pancreatic ductal cancer is poorly understood, there is an increasing body of published work, and preliminary data presented in this application suggesting that signaling pathways that control cell proliferation, differentiation, and apoptosis are dysregulated in pancreatic cancer. The mechanistic experiments outlined in this proposal are 100% relevant to pancreatic cancer and will test the central hypothesis that overexpression of GSK-3$ contributes to pancreatic cancer cell proliferation and survival and is thus a viable therapeutic target. We hypothesize that: (a) the GSK-3¿ gene is gained or amplified in a subset of patients with pancreatic cancer; (b) oncogenic K-Ras signaling regulates the expression of the GSK-3¿ promoter through its effects on Ets-1, Ets-2 and AP-1 transcription factors; (c) c-Src is a regulator of GSK-3¿ protein overexpression; (d) GSK-3 is required for the development of PDA in the LSL-KRasG12D mouse model of pancreatic cancer; (e) enzastaurin will inhibit GSK-3 function in vivo. In order to test these hypotheses we will (1) TO DETERMINE THE MECHANISM REGULATING THE EXPRESSION OF GSK-30 IN PANCREATIC ADENOCARCINOMA.; (2) DETERMINE THE REQUIREMENT FOR GSK-3¿ IN PANCREATIC CANCER PATHOGENESIS.; (3) PERFORM A PHASE II STUDY OF ENZASTAURIN AND GEMCITABINE IN UNTREATED, METASTATIC PANCREATIC CANCER PATIENTS WITH METASTASES AMENABLE TO BIOPSY. Together, the studies outlined in this proposal will provide invaluable information on the mechanisms regulating the expression of GSK-3¿ in pancreatic cancer, the role of GSK-3¿ in pancreatic cancer development and the effect of GSK-3 inhibition in the treatment of pancreatic cancer. Additionally, there is increasing evidence that GSK-3¿ participates in many human malignancies, thus, information obtained in the studies performed in this proposal might advance our understanding of this kinase in other human neoplasms.