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Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers

Item Type:Article
Title:Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers
Creators Name:Fichtner, I. and Rolff, J. and Soong, R. and Hoffmann, J. and Hammer, S. and Sommer, A. and Becker, M. and Merk, J.
Abstract:PURPOSE: It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers. EXPERIMENTAL DESIGN: Starting from 102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T(2)/T(3)), 25 transplantable xenografts were established and used for further investigations. RESULTS: Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status. The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1 of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were >50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models. CONCLUSION: An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.
Keywords:Monoclonal Antibodies, Antineoplastic Agents, Phytogenic Antineoplastic Agents, Carboplatin, Large Cell Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Carcinoma, Deoxycytidine, Animal Disease Models, Neoplasm Drug Resistance, Etoposide, Gene Expression Profiling, ras Genes, Immunoblotting, Lung Neoplasms, Mutation, Oligonucleotide Array Sequence Analysis, Paclitaxel, Polymerase Chain Reaction, Prognosis, Protein Kinase Inhibitors, Quinazolines, Radiation-Sensitizing Agents, Epidermal Growth Factor Receptor, Small Cell Lung Carcinoma, Biological Tumor Markers, Tumor Suppressor Protein p53, Vinblastine, Xenograft Model Antitumor Assays, Animals, Mice
Source:Clinical Cancer Research
Publisher:American Association for Cancer Research
Page Range:6456-6468
Date:15 October 2008
Official Publication:https://doi.org/10.1158/1078-0432.CCR-08-0138
PubMed:View item in PubMed

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