Adjuvant therapy for patients with newly diagnosed glioblastoma

Glioblastoma (GBM) is one of the most lethal tumors in the adult, with no evident changes in survival over the years, despite substantial improvement in surgical and radiotherapy techniques. The chemotherapy options have been limited for the upfront treatment, relying on a single alkylating agent Temozolomide (TMZ). TMZ is known to improve treatment response and survival of patients whose tumors have MGMT (O6- methylguanine-DNA methyltransferase) promoter methylation. In recent years, research has focused on identifying small-molecules inhibitors of receptors tyrosine kinase that are mutated or amplified in GBM, and on their dysregulated signaling transduction pathways. Although these pathways and receptors have been attractive targets for treatment of GBM, the small-molecules inhibitors have not demonstrated success in clinical trials. Inter-tumor and intra-tumoral heterogeneity are a main hurdle towards designing effective therapeutic options. Another appealing effort on finding new treatments for GBM treatment has been the inhibition of angiogenesis. It is well established that the interaction between tumor cells with pre-existing blood vessels leading to the formation of new blood vessels, a phenomenon called angiogenesis, is essential for the GBM growth. The angiogenesis inhibitor bevacizumab, a neutralizing antibody to VEGF-A, failed to show improvement in overall survival, and only revealed prolongation of progression-free survival in one of the two large multicenter trials that were performed in patients with newly diagnosed GBM, in combination with the standard of treatment of TMZ. To halt neoangiogenesis, the proliferation of capillary endothelial cells that sustains GBM proliferation, will require a better understanding of the paracrine interaction of endothelial cells with tumor cells and tumor initiating cells at the vascular niche, the participating trophogens and released chemokines, including immunologic messenger molecules from the tumor microenvironment. Other treatment modalities that apply practical physics to biology using alternating electrical fields are being explored for the newly diagnosed GBM patients.