Re-thinking the preclinical development of GBM therapeutics

Glioblastoma multiforme (GBM) remains one of the most incurable cancers. Although the genomic era has produced massive quantities of data in an attempt to characterize its molecular drivers[1, 2], these advances have yet to be effectively translated into clinical impact. In fact, several studies have identified the presence of all three GBM molecular subtypes within a single patient tumor[3, 4], illustrating the complexity of designing personalized medicine approaches. In addition to the strong intra/inter-tumoral heterogeneity, the inability of targeted therapies to achieve long-term remissions is likely a function of multiple complicating factors, including the presence of glioblastoma stem cells, redundant signaling pathways, the unique infiltrative nature of GBM cells, and difficulties associated with drug delivery across the blood-brain-barrier. New strategies to match patients to molecularly targeted therapies will also need to overcome these challenges imposed by the challenging GBM microenvironment within the brain