Table 1. Activated pathways in GBM; biomarkers and potential therapeutic opportunities.
| Biomarker | Pathway activated | Prognostic significance | Predictive significance | Ref | |
|---|---|---|---|---|---|
| MGMT | |||||
| MGMT methylation | Defects in DNA repair mechanisms | Better survival | Better response to TMZ | (32,33) | |
| mTOR2/SGK1/NDRG1 activation | MGMT stabilization | – | NDRG1 expression more predictive for response to TMZ than MGMT | (35) | |
| IDH | |||||
| IDH mutations | Affect DNA repair mechanisms | Better survival | Better response to TMZ; under debate | (46-48) | |
| EGFR | |||||
| EGFRvIII mutation | AKT, ERK and STAT3 | – | EGFR TKIs not successful in GBM. Interesting results with dacomitinib | (49-52) | |
| HB-EGF/EGFR wild type/EGFRvIII crosstalk | Prolonged STAT3 activity in the nucleus | – | EGFR antibody [528] that blocks binding of ligand to wild type EGFR. Targeting EGFR in conjunction with STAT3 | (53,55) | |
| EGFRvII mutation | Activation of AKT and STAT3 | – | Enhanced sensitivity to EGFR TKIs | (56,57) | |
| mTOR/SREBP-1/LDLR pathway | Tumor biosynthesis | – | Sensitivity to GW3965 (LXR agonist) | (59) | |
| NFκB | |||||
| NFκB activation | Expression of genes involved in inflammation, immune response, proliferation, and apoptosis | – | Disappointing results with NFκB-targeting drugs | (60,61) | |
| NFKBIA deletion | Mutually exclusive with EGFR amplification. NFκB suppression gene | NFKBIA/MGMT: 2-gene model associated with prognosis | Restoration of NFKBIA expression: sensitivity to chemotherapy | (62) | |
| IL-6/SphK1/S1P/S1PR1axis | NFκB and STAT3 activation | – | FTY270: SphK1 and S1PR1inhibitor | (63) | |
| PDCD4downregulation | Inhibits NFκB-dependent transcriptional activity | – | Potential alternative target for NFκB inhibition | (68) | |
| AEG1 | |||||
| AEG1 overexpression | PI3K-AKT, MAPK/ERK, Wnt, and NFκB activation. EAAT2 inhibition | – | Potential target for GBM therapy | (70-72,74) | |
| Other biomarkers | |||||
| AXL/Mer overexpression | – | – | AXL or Mer inhibitors | (75,76) | |
| EZH2 overexpression | AXL overexpression, | – | HDAC inhibitors | (77-79) | |
| STAT3 activation | |||||
| FIG-ROS fusion | – | – | ROS as a therapeutic target | (80,81) | |
| FGFR1-TACC1 and FGFR3-TACC3 fusions | – | – | FGFR inhibitors | (82) | |
| PTPRU (non-full-length isoforms) | β-catenin signaling activation | – | – | (83) | |
| TRIM3 loss | Musashi/Numb/NICD/Notch/Hedgehog pathway c-Myc expression | – | – | (87) | |
TMZ, temozolomide; EGFR, epidermal growth factor receptor; MGMT, methylguanine methyltransferase; IDH, isocitrate dehydrogenase; AEG1, astrocyte elevated gene-1; GBM, glioblastoma multiforme; TKIs, tyrosine kinase inhibitors; LXR, liver X receptor; FGFR, fibroblast growth factor receptor.