Overview of the Molecular Genetics and Molecular Chemotherapy of GBM

Abstract

Glioblastoma multiforme (GBM) remains refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neurooncology has now begun to clarify the transformed phenotype of GBM and identify oncogenic pathways that might be amenable to small molecule and antibody “targeted” therapy. Growth factor signaling pathways are often upregulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation of GBM include Raf, MEK, PI3K, Akt, and mTOR. In addition, overactivity of vascular endothelial growth factor (VEGF) and other effectors leads to neoplastic angiogenesis. “Targeted” therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (e.g., imatinib, erlotinib) and farnesyltransferase inhibitors (e.g., tipifarnib). Molecular therapeutic small molecules specific to Raf, PI3K, and mTOR include sorafenib, LY294002, and CCI-779, respectively. “Targeted” antiangiogenesis approaches include monoclonal antibodies to VEGF (e.g., bevacizumab) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (e.g., vatalanib, sunitinib). Further development of “targeted” therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life for patients with GBM.