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。放射治疗是局部晚期非小细胞肺癌（NSCLC）的主要治疗方式之一，无论是单独治疗还是联合全身化疗。最近，由于对肺癌发生中涉及的分子致癌驱动因素有了更好的理解，临床上开发了靶向全身治疗，以在遗传分层的肺癌患者人群中产生更高的缓解率和更长的总生存期。例如，与常规化疗相比，厄洛替尼和吉非替尼在携带选择性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NSCLC中特定致癌驱动因素如何影响其对放射疗法或联合放化疗的敏感性的理解有限，并且尚未在临床前进行系统的体内研究。在该提议中，如以下具体目标中所概述的，我们提议采用我们充分表征的肺癌基因工程小鼠模型，其基于常见肺癌相关致癌驱动因子的诱导性肺上皮特异性表达（EGFR激酶结构域突变体，EGFRvIII突变体和KRAS突变体）沿着最新的小动物局灶性辐照器平台，以剖析定义的致癌基因驱动的肺癌对放射治疗的不同敏感性，体内联合放化疗。成功完成目标的数据将有助于识别对放射敏感的基因型特异性肺癌，有助于合理整合放射治疗与靶向治疗，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.