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.
| Walter, Annette O; Sjin, Robert Tjin Tham; Haringsma, Henry J et al. (2013) Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 3:1404-15 |
| Walrath, Jessica C; Hawes, Jessica J; Van Dyke, Terry et al. (2010) Genetically engineered mouse models in cancer research. Adv Cancer Res 106:113-64 |
