BACKGROUND: The differential outcomes of clinical studies of the targeted therapies for non-small cell lung cancer (NSCLC) indicate that better stratification of patients is required. This could be achieved with the help of patient-derived xenografts (PDX) of epidermal growth factor receptor (EGFR) wild-type patients resistant to erlotinib treatment. OBJECTIVE: To explore the potential of patient-derived NSCLC xenografts to optimize therapy using 24 well-characterized early-stage NSCLC PDX. METHOD: Patient tumor tissue was transplanted subcutaneously into nude mice. After engraftment, tumors were expanded and the sensitivity was tested. Gene expression analysis was used to identify differentially expressed genes between erlotinib responder (n = 3) and non-responder (n = 21). Tumor tissue was analyzed with TaqMan PCR, immunohistochemistry and ELISA to examine the response of the models. RESULTS: Gene expression analysis revealed vascular endothelial growth factor A (VEGFA) to be up-regulated in erlotinib non-responder. Because of that, the combination of erlotinib with bevacizumab was evaluated in one erlotinib-sensitive and four erlotinib-resistant PDX. Combination treatment was superior to monotherapy, leading to the highest and significant inhibition of tumor growth in all models investigated. A decline of VEGFA protein and an increase of VEGFA-mRNA were observed after bevacizumab treatment. Bevacizumab treatment resulted in a distinct decrease of blood vessel number. CONCLUSION: This study showed that with the help of preclinical PDX models, drug combinations for therapy improvement can be identified on a rational basis. It was observed that a dual blockage of EGFR and VEGFA was more effective than a monotherapy for the treatment of NSCLC in selected PDX models. PDX could be employed to optimize the treatment of cancer patients.
BACKGROUND: The differential outcomes of clinical studies of the targeted therapies for non-small cell lung cancer (NSCLC) indicate that better stratification of patients is required. This could be achieved with the help of patient-derived xenografts (PDX) of epidermal growth factor receptor (EGFR) wild-type patients resistant to erlotinib treatment. OBJECTIVE: To explore the potential of patient-derived NSCLC xenografts to optimize therapy using 24 well-characterized early-stage NSCLC PDX. METHOD:Patienttumor tissue was transplanted subcutaneously into nude mice. After engraftment, tumors were expanded and the sensitivity was tested. Gene expression analysis was used to identify differentially expressed genes between erlotinib responder (n = 3) and non-responder (n = 21). Tumor tissue was analyzed with TaqMan PCR, immunohistochemistry and ELISA to examine the response of the models. RESULTS: Gene expression analysis revealed vascular endothelial growth factor A (VEGFA) to be up-regulated in erlotinib non-responder. Because of that, the combination of erlotinib with bevacizumab was evaluated in one erlotinib-sensitive and four erlotinib-resistant PDX. Combination treatment was superior to monotherapy, leading to the highest and significant inhibition of tumor growth in all models investigated. A decline of VEGFA protein and an increase of VEGFA-mRNA were observed after bevacizumab treatment. Bevacizumab treatment resulted in a distinct decrease of blood vessel number. CONCLUSION: This study showed that with the help of preclinical PDX models, drug combinations for therapy improvement can be identified on a rational basis. It was observed that a dual blockage of EGFR and VEGFA was more effective than a monotherapy for the treatment of NSCLC in selected PDX models. PDX could be employed to optimize the treatment of cancerpatients.
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Authors: Dennis Gürgen; Theresia Conrad; Michael Becker; Susanne Sebens; Christoph Röcken; Jens Hoffmann; Stefan Langhammer Journal: Commun Biol Date: 2022-01-17