FAK and IGF-1R interaction in pancreatic cancer survival

描述(由申请人提供)：这个拟议的五年培训计划旨在扩大申请人在高级分子生物学方面的知识，目标为：1)在体外和体内模型中寻求以假设为驱动的、机制的理解，即粘着斑激酶(FAK)和胰岛素样生长因子受体(IGF-1R)在促进胰腺癌细胞存活中的作用；以及2)为申请人提供所需的技能，以开发应用靶向分子疗法的翻译研究计划。培训部分经过整合和精心设计，以帮助申请者实现其长期职业目标，即开发了解癌细胞生物学的成功独立研究计划，并开发癌症治疗的新分子方法。 胰腺癌在美国仍然是一个尚未解决的主要健康问题，该疾病患者的死亡率与发病率相似。这种疾病需要新的治疗方法来提高患者的存活率。FAK和IGF-1R均为酪氨酸激酶，在胰腺癌中过表达。二者都被认为是肿瘤细胞抵抗细胞凋亡的重要生存信号，也是肿瘤细胞侵袭和增殖的促进剂。将被检验的假设是激活的IGF-1R、IRS-1(IGF-1R信号的关键介质)和FAK是否作为人胰腺癌细胞重要的生存信号在物理上相互作用和协同作用。概述的研究将试图阐明FAK和IGF-1R在这些细胞中相互作用的机制，并确定同时抑制FAK和IGF-1R是否会更有效地抑制细胞的侵袭、黏附、增殖和促进细胞凋亡。将使用GST和HIS融合蛋白来评估FAK、IRS-1和IGF-1R之间的结合结构域。FAK和IGF-1R抑制后被激活的凋亡通路将被确定。FAK和IGF-1R的活性将被选择性小分子酪氨酸激酶抑制剂的使用和显性阴性形式的表达所抑制。小分子酪氨酸激酶抑制剂FAK和IGF-1R抑制人胰腺肿瘤生长的能力将在裸鼠动物模型中进行研究。 这项应用代表了针对人类胰腺癌这两种激酶的首次尝试。

DESCRIPTION (provided by applicant): This proposed five-year training program seeks to expand the applicant's knowledge in advanced molecular biology with the goals of: 1) pursuing a hypothesis-driven, mechanistic understanding, in both in vitro and in vivo models, of the role of focal adhesion kinase (FAK) and insulin-like growth factor receptor (IGF-1R) in promoting pancreatic cancer cell survival; and 2) to provide the applicant with the skills needed to develop a translational research program for the application of targeted molecular therapeutics. Training components have been integrated and thoughtfully constructed to help the applicant reach his long-term career goal of developing a successful independent research program that understands cancer cell biology and develops novel molecular approaches to cancer treatment. Pancreatic cancer remains a major unsolved health problem in the United States with the death rate of patients with this disease similar to the incidence. Novel therapies are needed in this disease to improve patient survival. FAK and IGF-1R are tyrosine kinases whose overexpression occurs in pancreatic cancer. Both have been reported to be important survival signals for tumor cells to resist apoptosis as well as promoters of invasion and proliferation. The hypothesis that will be tested is whether activated IGF-1R, IRS-1 (critical mediator of IGF-1R signaling) and FAK physically interact and synergize as important survival signals in human pancreatic adenocarcinoma cells. Studies outlined will seek to elucidate the mechanism of interaction between FAK and IGF-1R in these cells and to determine if inhibition of both FAK and IGF-1R simultaneously will more efficiently inhibit cell invasion, adhesion, proliferation and potentiate apoptosis. Binding domains between FAK, IRS-1 and IGF-1R will be evaluated with the use of GST and HIS fusion proteins. Apoptotic pathways that are activated following FAK and IGF-1R inhibition will be determined. FAK and IGF-1R activity will be inhibited with the use of selective small molecule tyrosine kinase inhibitors and with the expression of dominant negative forms to both. The ability of small molecule tyrosine kinase inhibitors of FAK and IGF-1R to inhibit growth of human pancreatic tumors, will be studied in a nude mouse animal model. This application represents the first attempts at targeting both of these kinases in human pancreatic cancer.