| Anti-angiogenic therapies, although promising in pre-clinical studies, have had somewhat disappointing results in human trials. In particular, data now suggest that some tumors may be resistant to the anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) bevacizumab. Thus, the use of anti-VEGF monotherapy has had limited clinical success. The variation of tumor responses to anti-angiogenic therapy suggests a complex mechanism of drug action within different tumors. Therefore, the success of anti-VEGF therapy for the treatment of cancer may rely on a better understanding of genes associated with responsiveness or resistance. We hypothesize that differences in gene expression of lung cancer cell lines determine sensitivity or resistance to anti-VEGF therapies. We will address this with the following Aims: 1)To evaluate the growth of lung cancer cell lines in response to anti-VEGF therapy in vivo; 2) To analyze gene expression signatures of lung cancer cell lines that are resistant and sensitive to anti-VEGF therapy in vivo. Since anti-VEGF strategies primarily target tumor vasculature, which is difficult to recapitulate in vitro, the effect of anti-VEGF therapies on tumor cell gene expression must be evaluated in vivo. Therefore, a subset of lung cancer cell lines (n=12) will be used in mouse xenograft models. Tumor-bearing mice will be treated with anti-VEGF mAbs, bevacizumab or r84. r84 is a fully human anti-VEGF mAb characterized in the Brekken laboratory. Microarray analysis of gene expression of sensitive and resistant tumor cell lines will be analyzed in an effort to develop a gene signature to predict sensitivity to anti-VEGF therapy. The resulting gene signature will be tested against independent lung cancer cell lines (n=6-10) that will be evaluated in vivo for sensitivity to anti-VEGF therapy.
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