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，在美国每年造成超过150，000人死亡，在全世界每年造成超过100万人死亡。非小细胞肺癌占所有肺癌病例的80%以上。因此，开发新的靶向治疗非小细胞肺癌的药物具有重要的临床和公共卫生意义。近年来，靶向癌症治疗的出现导致癌症患者的预后和生存方面的重大进展。我们的申请人团队为这些进展中最引人注目的一项做出了贡献，即为肺癌携带激活EGFR突变的患者部署EGFR抑制剂。这导致了对这些患者的治疗取得了重大进展，正如去年的几项临床试验所证明的那样。然而，正如仍然严峻的死亡率统计数据所显示的那样，摆在我们面前的努力远远超过了我们和其他调查人员迄今为止所取得的成就。该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。具体来说，我们将根据每个肺癌激酶靶点（EGFR，TBK1和DDR2）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治疗剂进行体内治疗功效研究。最后，我们将使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.