Preclinical Characterization of Drugs in Mouse Model of Lung Cancer

小鼠肺癌模型中药物的临床前表征

• 批准号: 8349406
• 负责人: Terry van Dyke
• 金额: $ 124.21万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349406
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Adopted; Animal Diseases; Animal Model; Animals; Antineoplastic Agents; Bioinformatics; Biological Markers; Blood specimen; Brain; California; Cancer Center; Cancer Model; Clinical; Clinical Management; Clinical Trials; Collection; Communities; Complex; Data; Data Set; Databases; Disease; Disease Progression; Drug Delivery Systems; Drug resistance; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Experimental Neoplasms; Foundations; Future; Gefitinib; Generations; Genes; Genetic; Genetically Engineered Mouse; Goals; Human; Image; Laboratories; Liquid substance; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic Marker; Metabolic Pathway; Methods; Modeling; Molecular; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Operative Surgical Procedures; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Preclinical Drug Evaluation; Production; Publications; Relapse; Resistance; Resources; Scientist; Services; Sirolimus; Squamous Cell; Squamous cell carcinoma; Staging; System; Systems Biology; Technology; Therapeutic; Therapeutic Effect; Thoracic Oncology; Tissue Sample; Tissues; Tyrosine Kinase Inhibitor; Universities; Xenograft procedure; base; biobank; cancer type; chemotherapy; clinically relevant; cohort; comparative; design; drug testing; efficacy evaluation; epidemiologic data; human FRAP1 protein; in vivo; insight; lung Carcinoma; lung tumorigenesis; mouse model; mutant; novel; oncology program; pre-clinical; pre-clinical research; preclinical efficacy; preclinical evaluation; protein metabolite; receptor; research study; tool; tumor

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.

肺癌代表最常见的恶性肿瘤形式，占全球所有癌症临床病例的约25%，并且是发生率稳步增加的少数癌症类型之一。非小细胞肺癌（NSCLC）是临床治疗中具有挑战性的肿瘤类型，在初次手术/治疗后经常复发耐药癌症，并具有显著的转移潜力。为了深入了解肺癌形成的分子基础和复发期耐药的原因，该中心成功采用并表征了两种已建立的NSCLC模型。一种模型利用TetOn诱导系统在肺上皮细胞中特异性激活EGFR突变体形式（携带已知对吉非替尼不敏感的T790 M突变）的表达，该突变体形式在临床病例中与腺癌的化疗抗性形式相关，而第二种模型允许Kras途径的条件性过度激活，同时使LKB基因失活，导致鳞状细胞癌最终转移到脑。这两种模型已成功地扩大和遗传方法的发展，以合理生产的实验队列。CAPR科学家在一项大规模实验中采用了前一种模型，以评估不可逆受体酪氨酸激酶（RTK）抑制剂BIBW 2992以及该化合物与mTOR受体雷帕霉素的组合的治疗效果。平行地，诱导相同动物模型的第二组形成肺肿瘤，并且为了鉴定指示早期疾病的新的大分子和代谢标志物的目的，也从疾病前动物进行血液和组织样品的频繁纵向收集。目前，来自这两个实验的数据已被系统地分析，也通过生物信息学工具的应用，并在肺肿瘤发生过程中发现失调的代谢和途径组分的数据已准备出版。