Preclinical Characterization of Drugs in Mouse Model of Lung Cancer

肺癌是最常见的恶性肿瘤，约占全世界所有癌症临床病例的25%，是少数几种发病率稳步上升的癌症类型之一。非小细胞肺癌（NSCLC）被证明是临床治疗中具有挑战性的肿瘤类型，其在初始手术/治疗后经常复发耐药癌症，并且具有突出的转移潜力。为了深入了解肺癌形成的分子基础和复发期耐药的原因，美国高级临床前研究中心成功采用了两种已建立的非小细胞肺癌模型，并对其进行了表征。一种模型利用TetOn诱导系统特异性激活肺上皮细胞中与腺癌化疗耐药形式相关的EGFR突变形式的表达（含有已知对吉非替尼不敏感的T790M突变），而第二种模型允许Kras途径的条件过度激活，同时使LKB基因失活，导致鳞状细胞癌最终转移到大脑。这两个模型已经成功地扩展和遗传方法发展到合理的生产实验队列。CAPR科学家在大规模实验中采用前一种模型来评估不可逆受体酪氨酸激酶（RTK）抑制剂BIBW2992及其与mTOR抑制剂雷帕霉素的联合治疗效果。与此同时，同一动物模型的第二个队列已被诱导形成肺肿瘤，并进行了频繁的血液和组织样本的纵向收集，也来自疾病前期的动物，目的是确定指示早期疾病的新的大分子和代谢标志物。目前，我们已经对两个实验的数据进行了系统的分析，并运用生物信息学工具，对在肺肿瘤发生过程中发现的代谢和通路成分失调的数据已经准备发表。2012年4月，在CAPR高级员工和上汽集团业务发展办公室的持续努力下，与一家行业合作伙伴（由CRADA机制支持）启动了一个多层次项目，旨在评估下一代RTK抑制剂化合物在由异常EGFR信号驱动的CAPR NSCLC模型中的作用。该项目第一个里程碑的实验部分预计将于2012年9月底完成。

Lung cancer represents the most frequent form of malignancy comprising about 25% of all cancer clinical cased worldwide and being one of few cancer types with steadily increasing occurence. Non-small cell lung carcinomas (NSCLC) are proven to be challenging tumor type for clinical management with frequent re-occurence of drug resistant cancer after initial surgery/therapy and prominent metastatic potential. To gain in-depth insight into the molecular basis of lung carcinoma formation and reasons for drug resistance in relapse phase, the Center for Advanced Preclinical Research successfully adopted and characterized two established models of NSCLC. One model exploits TetOn inducible system to activate specifically in lung epithelial cells the expression of mutant form of EGFR (harboring T790M mutation known to be insensitive to gefitinib) related in clinical cases to chemotherapy resistant form of adenocarcinoma, whereas the second model allows for conditional overactivation of Kras pathway while inactivating LKB gene resulting in squamous cell carcinimas eventually metastatizing to the brain. Both models have been successfully expanded and genetic approaches developed to rational production of experimental cohorts. CAPR scientists employed the former model in a large scale experiment to evaluate the therapeutic effect of an irreversible receptor-tyrosine kinase (RTK) inhibitor BIBW2992 and a combination of this compound with mTOR inhibotor rapamycin. In parallel, a second cohort of the same animal model has been induced to form lung tumors and a frequent longitudinal collection of blood and tissue samples has been performed, also from pre-disease animals, for the purpose of identifying novel macromolecular and metabolic markers indicative of early stage disease. At present, data from both experiments have been systematically analyzed, also via application of bioinformatics tools, and the data on discovered metabolic and pathway components found disregulated in the course of lung tumorigenesis have been prepared for publication. In April 2012, persistent outreach efforts of CAPR sr. staff and SAIC-F business development office resulted in launching a multi-tier project with an industry collaborator (supported by CRADA mechanism) aimed at evaluating next generation RTK inhibitor compound in CAPR NSCLC model driven by aberrant EGFR signaling. The experimental part of the project first milestone is expected to be completed by teh end of September 2012.