Abstract
Glioblastoma (GBM) is the most prevalent and deadliest form of primary malignant brain tumor in adults. Radiation associated with chemotherapy following maximal feasible surgery is the standard of care. However, it remains an incurable disease with inexorable recurrence after multimodal therapy due to several factors including tumor aggressiveness with high degree of tumor cell infiltration into surrounding brain tissue, high proliferation, molecular heterogeneity and radioresistance. A better understanding of the tumor biology may allow development of new strategies to overcome treatment resistance. Overcoming radioresistance in GBM has been considered as a challenge for decades. In this systematic review we aim to summarize biologic pathways and mechanisms of therapeutic resistance involved in GBM and try to define some potential future therapeutic perspectives. The main mechanisms of radioresistance that we will discuss are hypoxia, the subpopulation of cancer stem cells in GBM, and the epidermal growth factor receptor (EGFR) expression. We will also focus on the potential role of innovative approaches, such as targeted therapy, nanoparticles and non-photon radiotherapy.