Preclinical Characterization of Drugs in Mouse Model of Lung Cancer

肺癌是最常见的恶性肿瘤，约占全世界所有临床病例的25%，是发病率稳步上升的为数不多的癌症类型之一。非小细胞肺癌(NSCLC)是临床治疗中极具挑战性的肿瘤类型，首次手术/治疗后耐药肿瘤复发频繁，转移潜能显著。为了深入了解肺癌形成的分子基础和复发期耐药的原因，高级临床前研究中心成功地采用并表征了两个已建立的非小细胞肺癌模型。一种模型利用Teton诱导系统在肺上皮细胞中特异性地激活突变形式的EGFR(含有已知对吉非替尼不敏感的T790M突变)的表达，而第二种模型允许有条件地过度激活Kras途径，同时灭活LKB基因，导致鳞癌最终转移到脑。这两个模型都得到了成功的扩展，并开发了遗传方法来合理地生产实验队列。CAPR的科学家在一项大规模实验中使用了前一种模型，以评估不可逆转的受体酪氨酸激酶(RTK)抑制剂BIBW2992以及该化合物与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，并进行了频繁的纵向血液和组织样本采集，也来自疾病前动物，目的是识别指示早期疾病的新的大分子和代谢标记物。目前，这两个实验的数据都已经通过应用生物信息学工具进行了系统的分析，并已准备好发表在肺肿瘤发生过程中发现的代谢和途径成分的数据。

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.