Targeted therapies for malignant gliomas

Malignant gliomas are the most lethal brain tumors, accounting for 13,140 deaths in the United States each year [1]. Despite significant advances in treatment, malignantgliomas remain incurable and carry a dismal prognosis. The median survival of patientswith glioblastoma is only 15 months from diagnosis with standard treatment [2]. Untilrecently, the role of chemotherapy has been questionable but temozolomide has nowbecome the standard of care for treatment of newly diagnosed glioblastoma concurrentlywith external beam radiation therapy. An increased understanding of the molecularpathogenesis of malignant gliomas has led to the development of a number of targetedtherapies with encouraging results in early studies. Most of these agents are directedagainst angiogenesis or growth factor pathway ligands, their receptors, or intracellularsecond messenger pathways involved in signal transduction. Single agent bevacizumab, ahumanized monoclonal antibody against the vascular endothelial growth factor (VEGF)ligand, was recently approved by the US Food and Drug Administration (FDA) fortreatment of recurrent glioblastoma. Not all malignant glioma patients respond to targetedtherapies and definitive predictive markers are lacking. Unfortunately, even forresponding patients, the responses are generally short-lived and malignant gliomasuniformly recur. An improved understanding of the mechanisms of resistance and therole of glioma stem cells in tumorigenesis is necessary to develop more effectivetherapies.