Glioma (KEGG map)

Gliomas are the most common primary brain tumours, more than 40 percent of central nervous system neoplasms, and include astrocytomas, oligodendrogliomas, mixed gliomas and ependymomas. KEGG map hsa05214 draws the routes to glioblastoma, the most malignant infiltrating astrocytoma. Primary glioblastoma arises de novo in older patients and typically shows EGFR amplification or mutation, p16 (CDKN2A) and p14ARF deletion and PTEN mutation or deletion. Secondary glioblastoma progresses from low-grade or anaplastic astrocytoma in younger patients and frequently shows PDGF and PDGFR over-expression, CDK4 or MDM2 amplification, TP53 mutation and RB1 loss. Both routes converge on the same effectors: RAS-ERK, PI3K-AKT (unleashed by PTEN loss), PLC-gamma/calcium signalling from EGFR and PDGFR, and loss of the p16-CDK4/6-RB and p14ARF-MDM2-p53 checkpoints.

Weller and colleagues, Nature Reviews Disease Primers, 2015 (doi:10.1038/nrdp.2015.17) review the field: IDH mutation separates lower-grade and secondary tumours from IDH wild-type primary glioblastoma, MGMT promoter methylation predicts benefit from temozolomide, and BRAF V600E and KIAA1549-BRAF fusions characterise many paediatric low-grade gliomas.

What drugs do about it: temozolomide with radiotherapy remains the standard for glioblastoma, with bevacizumab used for symptomatic control; vorasidenib treats IDH-mutant grade 2 glioma; in paediatric low-grade glioma the BRAF-MAPK arm is drugged with tovorafenib (listed by KEGG) and with dabrafenib plus trametinib for BRAF V600E tumours, and the MEK inhibitors selumetinib and mirdametinib treat NF1-related tumours. EGFR and PDGFR inhibitors have so far failed in glioblastoma, partly because of the blood-brain barrier and tumour heterogeneity.