Glioblastoma multiforme is a solid tumor with particular aspects due to its organ of origin and its development modalities. The brain is very sensitive to oxygen and glucose deprivation and it is the only organ that cannot be either transplanted or entirely removed. Furthermore, many clues and recent indirect experimental evidence indicate that the micro-infiltration of the whole brain parenchyma occurs in very early stages of tumor bulk growth or likely even before. As a consequence, the primary glioblastoma (IDH-wildtype, WHO 2016) is the only tumor where the malignant (i.e. distantly infiltrating the organ of origin) and deadly (i.e. leading cause to patient’s death) phases coincide and overlap in one single phase of its natural history. To date, the prognosis of optimally treated glioblastoma patients remains dismal despite recent fundamental progress in neurosurgical techniques which are enabling better maximal safe resection and survival outcome. Intratumor variegated heterogeneity of glioblastoma bulk due to trunk-branch evolution and very early micro-infiltration and settlement of neoplastic cells in the entire brain parenchyma are the reasons for resistance to current therapeutic treatments. With the aim of future innovative and effective therapies, this paper deals with the unique glioblastoma features, the appropriate research methods as well as the strategies to follow to overcome current causes of resistance.
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