Animal Models/Experimental Therapeutics Core

项目总结(见说明)： 肺癌是美国和全世界癌症死亡的主要原因，美国每年有超过15万人死于肺癌，全球每年有100多万人死于肺癌。非小细胞肺癌占所有肺癌病例的80%多一点。因此，发展新的靶向治疗非小细胞肺癌具有重要的临床意义和公共卫生意义。近年来，靶向癌症治疗的出现使癌症患者的预后和生存率取得了重大进展。我们的申请者小组为这些进步中最引人注目的一项做出了贡献，即为肺癌患者部署了EGFR抑制剂，这些患者携带激活的EGFR突变。这导致了这类患者的治疗取得重大进展，去年的几项临床试验证明了这一点。然而，仍然严峻的死亡统计数字表明，摆在我们面前的努力远远超过我们和其他调查人员迄今所取得的成就。这一综合研究计划的目标是推进非小细胞肺癌靶向治疗的科学基础。具体地说，我们将基于每个肺癌激酶靶点(EGFR、TBK1和DDR2)来生成和表征基因工程小鼠模型。然后，我们将使用这些小鼠模型和本计划中产生的适当匹配的靶向疗法进行体内治疗效果研究。最后，我们将用小鼠模型和分子抑制剂进行体内慢性治疗研究，以确定获得性耐药的体内机制。

PROJECT SUMMARY (See instructions): Lung cancer is the leading cause of cancer death in the United States and worldwide, accounting for over 150,000 deaths per year in the United States and over 1 million deaths per year world-wide. Non-small cell lung cancer accounts for slightly over 80% of all lung cancer cases. Therefore the development of novel targeted therapeutics for non-small cell lung cancer is of great clinical and public health importance. In recent years, the advent of targeted cancer therapies has led to major advances in the prognosis and survival of cancer patients. Our applicant group has contributed to one of the most dramatic of these advances, the deployment of EGFR inhibitors for patients whose lung cancers bear activating EGFR mutations. This has led to significant advances in treatment of such patients, as demonstrated in this last year by several clinical trials. Nevertheless, as shown by the still-grim mortality statistics, the efforts that lie in front of us far exceed the accomplishments that we and other investigators have achieved to date. The goal of this integrated research Program is to advance the scientific underpinnings of targeted therapies for non-small cell lung cancer. Specifically, we will generate and characterize genetically engineered mouse models based on each of the lung cancer kinase targets (EGFR, TBK1 and DDR2). We will then perform in vivo therapeutic efficacy studies using these mouse models and the appropriately matched targeted therapeutics generated in this Program. Lastly, we will perform in vivo chronic treatment studies with the mouse models and molecule inhibitors to determine in vivo mechanisms of acquired resistance.