From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress

Abstract

Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.

Multi‐omics analysis reveals the association between specific solute carrier proteins gene expression patterns and the immune suppressive microenvironment in glioma

“…Importantly, enrichment analysis consistently revealed the activation of pathways significantly enriched in the high‐risk group, with the high SLC43A3 expression group also showing significant enrichment of the PI3K‐AKT signalling pathway. In glioblastoma, receptor tyrosine kinases such as EGFR and VEGFR activate the PI3K‐AKT signalling pathway via tyrosine residue autophosphorylation, playing a pivotal role in tumour proliferation and progression 45 . Notably, in our cellular communication analysis, cells with high‐risk scores exhibited enhanced EGF and VEGF signalling pathway network activity.…”

“…Additionally, the high‐risk group displayed distinct metabolic pathway activities and differential responses to chemotherapy agents, with a higher resistance to temozolomide, carboplatin and axitinib and increased sensitivity to etoposide, topotecan, vincristine, methotrexate and procarbazine. Chemotherapy agents have traditionally been the frontline treatment for glioblastoma, while immunotherapy offers new hope in glioblastoma therapy 45,46 . Therefore, grouping based on the expression patterns of different SLCs may provide valuable guidance in the selection of chemotherapy and immunotherapy for patients.…”

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

“…Histone modification, a multifaceted process, involves diverse mechanisms such as lactylation, methylation, ubiquitination, acetylation, phosphorylation, and adenosine diphosphate (ADP) ribosylation [ 568 ], facilitated by various enzymes. Aberrations in histone modification contribute significantly to glioma progression, particularly histone acetylation and methylation in GBM [ 569 ]. EZH2, known as histone methyltransferase in polycomb repressive complex 2 (PRC2), modulates gene expression [ 570 , 571 ] by inhibiting PTEN and activating the NF-κB pathway in GBM [ 572 , 573 ].…”

“…Immune cells undergo metabolic adaptations associated with a tolerance phenotype, such as T cells relying on aerobic glycolysis and glutamine catabolism [ 585 ]. GBM, with heightened metabolic demands, presents an opportunity for treatment by targeting tumor metabolism [ 569 , 586 ]. The sodium/hydrogen exchanger 1 (NHE1), from SLC9A1, plays a pivotal role in keeping the microenvironment alkaline within the tumor, supporting aerobic glycolysis crucial for tumor progression [ 587 ].…”

Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives

“…Nitrosourea agents such as lomustine, simustine, formostine, carmustine, nimustine, and PCV (procarbazine + lomustine + vincristine) can cross the BBB and were first used for chemotherapy of gliomas. 42 , 43 Combination therapy consisting of cytotoxic chemotherapeutic agents such as teniposide, etoposide, isocyclophosphamide, cisplatin, and carboplatin has also been used occasionally. 2 , 44 , 45 Regimens are also used occasionally but the efficacy of these chemotherapy regimens is limited and their cytotoxic effects are significant.…”