Resistance mechanisms in glioblastoma stem cells: finding opportunities in challenges

Glioblastoma remains the most aggressive and devastating form of primary brain tumor with universally dismal survival outcomes despite multi-modality management, essentially rendering it incurable in contemporary neuro-oncologic practice. It displays all the classical hallmarks of cancer including immune suppression, sustained proliferative signalling, inhibition of apoptosis, angiogenesis and invasion (1,2). Glioblastoma is biologically very heterogeneous; this intra-tumoral heterogeneity is explained by the stochastic model (2,3), wherein the tumor arises from a single clone of cells with further progression resulting from random accumulation of somatic mutations in genetically unstable cell population and sequential selection of malignant sub-clones through micro-environment cues. The current standard of care for newly-diagnosed glioblastoma comprising maximal safe resection followed by post-operative focal conformal radiotherapy to the tumor bed with concurrent and adjuvant temozolomide chemotherapy, results in a median survival of around 15 months and a 5-year overall survival rarely exceeding 8–10% (4).