Emerging treatment strategies for glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5-year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small-molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population.

Keywords: biomarkers; brain imaging; cancer stem cells; epigenetics; glioblastoma multiforme (GBM).

Figure 1. Inhibition of 2-hydroxyglutarate production in heterozygotic IDH-1 cells

Wild-type IDH-1 converts isocitrate to alpha-ketoglutarate. Heterozygotic IDH-1 (R132H) mutant protein can convert alpha-ketoglutarate to 2-hydroxyglutarate, an onco-metabolite. Selective therapeutics against IDH-1 (R132H) prevent 2-hydroxyglutarate production while leaving normal IDH-1 enzymatic function intact.

Figure 2. Drug modification of epigenetic regulation

(A) Bromodomain readers recognize modified residues on histone tails which can lead to unraveling of the DNA/histone complex contingent on the bromodomain-containing complex composition. Unwound DNA is available for transcription complex interaction and transcription. (B) Unwound, transcriptionally active DNA reliant on bromodomain-containing complexes can be therapeutically targeted. Drugs blocking the bromodomain/histone tail modification interaction can prevent the helicase activity by bromodomain-containing complexes, thus stereohindering transcription regulators and silencing genes.