Fig. 1

Schematic representation of key regulatory pathways in implicated in gliomagenesis, and corresponding inhibitors that have been investigated in GBM. (A) PDGFR, VEGFR, EGFR as oncogenic receptors implicated in the angiogenesis axis. (i) Overexpression of PDGF and PDGFR in GBM cells collectively lead to increased tumour cell survival, growth, and migratory capability. (ii) Abnormal activation of the VEGFR pathway is responsible for the development of the characteristic leaky neovasculature found in GBM through promoting endothelial cell survival, differentiation, and migration, as well as encouraging microvascular formation. (iii) EGFR is commonly overexpressed in GBM and is implicated in improving tumour cell survival, growth, and proliferation through multiple pathways. (B) STAT3 can be activated by multiple receptors including IL-6 receptor, EGF, PDGF and HGF via the JAK/STAT signalling pathway. STAT3 activation is modulated by both upstream and downstream regulators. However, STAT3 is often upregulated in GBM cells, thus resulting in overexpression of STAT3 target genes, leading to gliomagenesis. (C) Overexpression of RTK and deficiency of the negative regulator PTEN in GBM cells collectively lead to the hyperactivation of AKT, which in turn mediates the activation of downstream kinases that regulate cell proliferation and protein synthesis. (D) Healthy cells depend on PARP to repair single-strand breaks. Inhibition of PARP-dependent DNA repair results in accumulation of double strand-breaks, which induce the activation of homologous recombination as the compensatory pathway to repair DNA damage. Oncometabolite D-2-HG blocks the activation of this compensatory pathway through induction of BRCAness, hence offering PARP as a synthetic lethality target in IDH-mutant GBM cells. Inhibition of all these targets (in red boxes) therefore serves as potential therapeutic approaches in treating GBM.