Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review)

Abstract

Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor and is associated with a poor clinical prognosis. Despite the progress in the understanding of the molecular and genetic changes that promote tumorigenesis, effective treatment options are limited. The present review intended to identify and summarize major signaling pathways and genetic abnormalities involved in the pathogenesis of GBM, as well as therapies that target these pathways. Glioblastoma remains a difficult to treat tumor; however, in the last two decades, significant improvements in the understanding of GBM biology have enabled advances in available therapeutics. Significant genomic events and signaling pathway disruptions (NF‑κB, Wnt, PI3K/AKT/mTOR) involved in the formation of GBM were discussed. Current therapeutic options may only marginally prolong survival and the current standard of therapy cures only a small fraction of patients. As a result, there is an unmet requirement for further study into the processes of glioblastoma pathogenesis and the discovery of novel therapeutic targets in novel signaling pathways implicated in the evolution of glioblastoma.

Keywords: glioblastoma; immunotherapy; mutations; signaling pathways; targeted therapy; tumor treating fields.

Figure 1

Mechanism of action of standard of care systemic therapeutic agents in glioblastoma multiforme. Temozolomide is converted to the short-lived active compound, MTIC. The cytotoxicity of MTIC methylase results in the methylation of guanine-rich areas of DNA, leading to inhibition of DNA replication and apoptosis. If the MGMT promoter is unmethylated, the alkyl group is removed from the DNA base guanine by MGMT protein. If the MGMT promoter is methylated, there is no active MGMT protein to repair it. Carmustine leads to interstrand crosslinking of DNA and RNA. The mechanism of action of beva-cizumab is to bind to VEGF-A and prevent its interaction with VEGFR tyrosine kinases VEGFR1 and VEGFR2 on the surface of endothelial cells. This leads to the inhibition of angiogenesis, proliferation, survival and migration of cells. Regorafenib is a multikinase inhibitor targeting several kinases (VEGFR1-3, TIE2, FGFR1 and 2, PDGFR, KIT, RAF and RET). MTIC, monomethyl triazeno imidazole carboxamide; FGFR fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.

Figure 2

Schematic representation of major molecular mechanisms involved in glioblastoma development. Binding of EGF to the EGFR results in activation of numerous downstream signaling pathways, including SOS1, GRB2 and PI3K-Akt-mTOR. Various extracellular factors lead to NF-κB activation. NF-κB dimers (p65-p50) are inactive in normal cells due to binding to IκB inhibitory factors in the cytoplasm, which blocks the nuclear localization sequence and prevents the transfer of NF-κB into the nucleus. In the nucleus, NF-κB dimers bind to κB-sites in the regulatory regions of genes participating in a wide range of cellular processes. Ras is a key player in the RTK-mediated PI3K/AKT and MAPK signaling pathways. The activation of all isoforms of RAS protein by the exchange of GDP with GTP results in the activation of MAPKs that also activate downstream ERK via phosphorylation. PI3K-activated AKT phosphorylates FOXO proteins at 3 serine/threonine residues, resulting in the promotion of nuclear exclusion and inactivation of the transactivation-dependent (genomic) tumor suppressor activities of FOXO proteins in the nucleus. Wnt signaling is inactivated in the absence of Wnt ligands. When inactive, cytoplasmic β-catenin is degraded by a β-catenin destruction complex, which includes Axin, adenomatosis polyposis coli, protein phosphatase 2A, GSK3 and casein kinase 1α. Phosphorylation of β-catenin within this complex by casein kinase and GSK3 targets it for ubiquitination and subsequent proteolytic destruction by the proteasomal apparatus. The active Wnt signaling pathway activates β-catenin, which is shuttled into the nucleus, leading to transcriptional activation of WNT signaling-target genes. SOS1, Son of Sevenless 1; GRB2l, growth factor receptor bound protein 2; GSK3, glycogen synthase kinase 3; GDP, guanosine diphosphate; FOX, forkhead box.