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Targeted Oncology
Published in: Targeted Oncology 4/2016

01-08-2016 | Original Research Article

Preclinical Study of a Combination of Erlotinib and Bevacizumab in Early Stages of Unselected Non-Small Cell Lung Cancer Patient-Derived Xenografts

Authors: J. Rolff, M. Becker, J. Merk, J. Hoffmann, I. Fichtner

Published in: Targeted Oncology | Issue 4/2016

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Abstract

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.
https://static-content.springer.com/image/art%3A10.1007%2Fs11523-015-0415-4/MediaObjects/11523_2015_415_Figa_HTML.gif
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Metadata
Title
Preclinical Study of a Combination of Erlotinib and Bevacizumab in Early Stages of Unselected Non-Small Cell Lung Cancer Patient-Derived Xenografts
Authors
J. Rolff
M. Becker
J. Merk
J. Hoffmann
I. Fichtner
Publication date
01-08-2016
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 4/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-015-0415-4

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