In vivo analysis of EGFR mutant driven lung cancers responses to radiation therap

描述(申请人提供)：肺癌是美国癌症相关死亡的主要原因。放射治疗是局部晚期非小细胞肺癌(NSCLC)的主要治疗方式之一，可单独或联合全身化疗。最近，由于对参与肺癌发生的分子致癌驱动因素有了更好的了解，临床上已经开发出有针对性的系统治疗方法，以在基因分层的肺癌患者群体中产生更高的应答率和更长的总生存期。例如，与传统化疗相比，erlotinib和gefitinib在携带选择性EGFR激酶域(KD)突变的非小细胞肺癌患者中产生了高达85%的应答率和更长的总生存期。然而，我们对NSCLC中特定的致癌驱动因素如何影响他们对放射治疗或联合化疗的敏感性的了解有限，临床前还没有在体内进行系统的研究。在这项建议中，正如下面具体目标所概述的那样，我们建议使用我们特征良好的肺癌基因工程小鼠模型，该模型基于常见肺癌相关癌基因驱动因素(EGFR激酶域突变、EGFRvIII突变和KRAS突变)的可诱导肺上皮特异性表达，以及最新的小动物焦点照射平台，在体内剖析已定义的癌基因驱动的肺癌对放射治疗和联合放化疗的差异敏感性。成功完成AIMS的数据将有助于识别对辐射敏感的基因特异性肺癌，有助于合理地将放射治疗与靶向治疗相结合，从而促进肺癌患者的护理和治疗。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer related deaths in the United States. Radiation therapy, either alone or in combination with systemic chemotherapy, is one of the main treatment modalities for locally advanced non-small cell lung cancer (NSCLC). Recently, driven by a better understanding of the molecular oncogenic drivers involved in lung tumorigenesis, targeted systemic therapies have been developed clinically to generate higher response rates and longer overall survival in a genetically stratified population of lung cancer patients. For example, erlotinib and gefitinib have produced up to 85 percent response rates and longer overall survival in patients with NSCLC who harbor selective EGFR kinase domain (KD) mutations when compared to conventional chemotherapies. However, our understanding of how specific oncogenic drivers in NSCLC impact their sensitivity to radiation therapy or combination chemo-radiation therapy is limited and has not been systematically studied in vivo pre- clinically. In this proposal, as outlined in the specific aims below, we propose to employ our well characterized genetically engineered mouse models of lung cancer based on inducible lung epithelium specific expression of the common lung cancer relevant oncogenic drivers (EGFR kinase domain mutants, EGFRvIII mutant and KRAS mutants) along with the latest small animal focal irradiator platform to dissect the differential sensitivity of the defined oncogene driven lung cancer to radiation therapy and combined chemo-radiation therapy in vivo. Data from the successful completion of the aims will help facilitate the identification of genotype specific lung cancers that are radiosensitive, help rationally integrate radiation therapy with targeted therapeutics and, thus, advance the care and treatment of lung cancer patients.