Molecularly targeted therapy in neuro-oncology

Abstract

During the past decade, the treatment paradigm for brain tumors has shift ed towards targeting molecular or genetic aberrations contributing to malignancy. Although brain metastases are more common, glioblastoma (GBM), the most common primary brain tumors in adults, has been center stage for development of molecularly targeted therapy in neuro-oncology. Most targeted agents explored in brain tumors are monoclonal antibodies and small-molecule kinase inhibitors. First-generation, single-targeted, kinase inhibitors have failed to demonstrate clinical benefit in unselected GBM populations. Mechanisms of resistance may include genetic heterogeneity, multiple kinase dependency, compensatory pathway activation, and limited delivery. Several strategies to overcome resistance have been developed simultaneously. In addition to tumor cells, therapies targeting the tumor microenvironment are also critical. As GBM is highly vascular tumor, antiangiogenic therapy may represent a novel treatment approach. Bevacizumab, a neutralizing monoclonal antibody of vascular endothelial growth factor, demonstrated significant clinical efficacy in patients with recurrent GBM and it was granted accelerated approval by the US Food and Drug Administration in 2009. Other targeted agents with antiangiogenic properties are currently under investigation in brain tumors. In this chapter, we will discuss the current status and future development of molecularly targeted therapy in neuro-oncology. © 2012 Elsevier B.V.