Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy

The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and av...

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Bibliographic Details
Published in:Clinical cancer research 2015-03, Vol.21 (5), p.1172-1182
Main Authors: Lee, Hye Won, Lee, Jung-Il, Lee, Se Jeong, Cho, Hyun Jung, Song, Hye Jin, Jeong, Da Eun, Seo, Yun Jee, Shin, Sang, Joung, Je-Gun, Kwon, Yong-Jun, Choi, Yoon-La, Park, Woong-Yang, Lee, Hyun Moo, Seol, Ho Jun, Shim, Young Mog, Joo, Kyeung Min, Nam, Do-Hyun
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Antineoplastic Agents - pharmacology
Brain Neoplasms - drug therapy
Brain Neoplasms - secondary
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Disease Models, Animal
Drug Screening Assays, Antitumor
Female
Gene Expression Profiling
Genotype
Humans
Inhibitory Concentration 50
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Male
Mice
Middle Aged
Molecular Targeted Therapy
Mutation
Neoplasm Grading
Neoplasm Staging
Precision Medicine
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins p21(ras) - genetics
Receptor Protein-Tyrosine Kinases - genetics
Receptor, Epidermal Growth Factor - genetics
Translational Medical Research
Xenograft Model Antitumor Assays
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Summary:The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies. We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment. NSCLC brain metastases (n = 34) showed a significantly higher successful PDX establishment rate than primary specimens (n = 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions. Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-14-1589