AI-14 * THE ANTI ANGIOGENIC AND INVASIVE EFFECTS OF AN INTEGRIN INHIBITOR AGAINST BEVACIZUMAB-INDUCED INVASIVE GLIOMA

Abstract

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in patients with glioblastoma. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor cell implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. We analyzed the three following groups: untreated, treated with bevacizumab, and treated with a combination of bevacizumab and cilengitide. Next, RNA was extracted from orthotopic U87ΔEGFR brain tumor models. The bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis using the microarray data demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the bevacizumab and cilengitide combination group. This study showed that that the combination of bevacizumab with cilengitide exerted its anti-invasive effect by suppressing the integrin-mediated cell adhesion pathway. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.