FAK and IGF-1R interaction in pancreatic cancer survival

描述（由申请人提供）：该拟议的五年培训计划旨在扩展申请人在先进分子生物学方面的知识，目标是：1）在体外和体内模型中，对粘着斑激酶（FAK）和胰岛素样生长因子受体（IGF-1 R）在促进胰腺癌细胞存活中的作用进行假设驱动的机制理解;以及2）为申请人提供开发用于靶向分子治疗的应用的转化研究计划所需的技能。培训内容已经整合并经过深思熟虑的构建，以帮助申请人实现其长期职业目标，即开发一个成功的独立研究计划，了解癌细胞生物学并开发新的分子方法来治疗癌症。 胰腺癌在美国仍然是一个主要的未解决的健康问题，患有这种疾病的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生存率。FAK和IGF-1 R是酪氨酸激酶，其过表达发生在胰腺癌中。两者都是肿瘤细胞抵抗凋亡的重要生存信号，也是肿瘤细胞侵袭和增殖的促进因子。将检验的假设是活化的IGF-1 R、IRS-1（IGF-1 R信号传导的关键介质）和FAK是否作为人胰腺癌细胞中的重要存活信号物理地相互作用和协同作用。概述的研究将试图阐明这些细胞中FAK和IGF-1 R之间相互作用的机制，并确定同时抑制FAK和IGF-1 R是否会更有效地抑制细胞侵袭、粘附、增殖和增强凋亡。将使用GST和HIS融合蛋白评价FAK、IRS-1和IGF-1 R之间的结合结构域。将测定FAK和IGF-1 R抑制后激活的凋亡途径。FAK和IGF-1 R活性将通过使用选择性小分子酪氨酸激酶抑制剂和通过对两者的显性负性形式的表达而被抑制。将在裸鼠动物模型中研究FAK和IGF-1 R的小分子酪氨酸激酶抑制剂抑制人胰腺肿瘤生长的能力。 该应用代表了在人胰腺癌中靶向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.