Therapeutic application of noncytotoxic molecular targeted therapy in gliomas: growth factor receptors and angiogenesis inhibitors

Growth factor receptors and angiogenesis play major roles in the oncogenesis of gliomas. Over the last several years, several noncytotoxic molecular targeted therapies have been developed against growth factor receptors and tumor angiogenesis. In gliomas, two main anti-growth factor receptor strategies have been evaluated in phase I/II clinical trials: (a) small molecule tyrosine kinase inhibitors (TKIs) and (b) monoclonal antibodies that target growth factors or growth factor receptors other than vascular endothelial growth factor (VEGF). Up to now, few glioma patients have responded to small TKIs (0%-14%) or monoclonal antibodies (three case reports) delivered as a single agent. Greater doses, combined therapies, as well as the identification of molecular biomarkers predictive of response and resistance are important in order to optimize drug delivery and improve efficacy. Antiangiogenic therapies are promising for the treatment of gliomas. Thalidomide and metronomic chemotherapy were the first antiangiogenic strategies evaluated, but they have shown only modest activity. Recent studies of bevacizumab, an anti-VEGF antibody, and irinotecan, a topoisomerase I inhibitor, have demonstrated a high response rate, suggesting that targeted antiangiogenic therapies may play a significant role in the management of high-grade gliomas in the future. However, the toxicity profiles of these agents are not fully defined and the radiological evaluation of possible tumor response is challenging. Clinical evaluation of several VEGF receptor TKIs is currently ongoing; one of these inhibitors, cediranib, has already demonstrated interesting activity as a single agent. The integrin inhibitor cilengitide represents another promising strategy.