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

描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因。放射治疗，单独或联合全身化疗，是局部晚期非小细胞肺癌（NSCLC）的主要治疗方式之一。最近，由于对参与肺肿瘤发生的分子致癌驱动因素有了更好的了解，临床上已经开发出靶向全身治疗，以在基因分层的肺癌患者群体中产生更高的反应率和更长的总生存期。例如，与传统化疗相比，厄洛替尼和吉非替尼在具有选择性EGFR激酶结构域（KD）突变的NSCLC患者中产生了高达85%的缓解率和更长的总生存期。然而，我们对非小细胞肺癌中特定的致癌驱动因素如何影响其对放射治疗或放化疗联合治疗的敏感性的理解是有限的，并且尚未在体内进行系统的临床前研究。在本提案中，正如下面的具体目标所概述的那样，我们建议采用基于常见肺癌相关致癌驱动因子（EGFR激酶结构域突变体）的诱导肺上皮特异性表达的基因工程小鼠肺癌模型，EGFRvIII突变体和KRAS突变体)以及最新的小动物局灶照射平台，以解剖确定的癌基因驱动的肺癌对放射治疗和放化疗联合治疗在体内的差异敏感性。成功完成这些目标的数据将有助于识别放射敏感的基因型特异性肺癌，有助于合理地将放射治疗与靶向治疗相结合，从而推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.