Use of axitinib, a new-generation tyrosine kinase inhibitor, to decrease glioblastoma growth despite primary resistance to the VEGF-antibody bevacizumab.

2077 Background: Targeted therapies are increasingly important in oncology. Axitinib is a novel orally available tyrosine kinase inhibitor which is mainly directed against the VEGFR family. VEGF-antibody bevacizumab is the acting drug of running clinical trials in glioblastoma. Methods: In immunodeficient mice, cell line- and patient-derived glioblastoma xenografts were established and treated with axitinib. Temozolomide, bevacizumab, and phosphate buffered saline served as controls. Tumor size, vascularization (CD31), vascular pericyte coverage (NG-2), apoptosis in tumor and endothelial cells as well as expression of EGFR, VEGFR1, VEGFR2, PDGFRβ, VEGF, and PlGF were determined. Experiments were approved by local ethics committee. Results: Positive control temozolomide always caused growth inhibition whereas primary resistances to bevacizumab as primary drug were observed. As most delighting result, axitinib caused a delay of tumor growth in a glioblastoma xenograft with primary resistance to bevacizumab. Tumor cell proliferation (Ki67) was significantly lower than in controls (p<.05). The number of CD31 positive endothelial cells decreased (p<.001). Numbers of NG2 positive pericytes were reduced (p<.001) and triple immunofluorescence showed a significant reduction of NG2 positive pericyte coverage of CD31 positive endothelial cells (p<.001). Expression of EGFR, PDGFRβ, and VEGFR1 proteins showed no alterations under axitinib treatment, but RT-PCR revealed a significantly decreased mRNA expression of VEGF-A and PlGF. Conclusions: Axitinib had significant effects on glioblastoma xenografts even with primary resistance to bevacizumab in a so far untreated tumor. There are currently two recruiting phase II trials with axitinib in glioblastoma multiforme. Further comparative studies with bevacizumab should urgently define the potential of this substance in glioblastoma therapy.