Emerging therapeutic strategies in glioblastsoma: drug repurposing, mechanisms of resistance, precision medicine, and technological innovations

Abstract

Glioblastoma (GBM) is an aggressive Grade IV brain tumor with a poor prognosis. It results from genetic mutations, epigenetic changes, and factors within the tumor microenvironment (TME). Traditional treatments like surgery, radiotherapy, and chemotherapy provide limited survival benefits due to the tumor's heterogeneity and resistance mechanisms. This review examines novel approaches for treating GBM, focusing on repurposing existing medications such as antipsychotics, antidepressants, and statins for their potential anti-GBM effects. Advances in molecular profiling, including next-generation sequencing, artificial intelligence (AI), and nanotechnology-based drug delivery, are transforming GBM diagnosis and treatment. The TME, particularly GBM stem cells and immune evasion, plays a key role in therapeutic resistance. Integrating multi-omics data and applying precision medicine show promise, especially in combination therapies and immunotherapies, to enhance clinical outcomes. Addressing challenges such as drug resistance, targeting GBM stem cells, and crossing the blood-brain barrier is essential for improving treatment efficacy. While current treatments offer limited benefits, emerging strategies such as immunotherapies, precision medicine, and drug repurposing show significant potential. Technologies like liquid biopsies, AI-powered diagnostics, and nanotechnology could help overcome obstacles like the blood-brain barrier and GBM stem cells. Ongoing research into combination therapies, targeted drug delivery, and personalized treatments is crucial. Collaborative efforts and robust clinical trials are necessary to translate these innovations into effective therapies, offering hope for improved survival and quality of life for GBM patients.

Keywords: Artificial intelligence; Blood–brain barrier; Nanotechnology; Next-generation sequencing; Precision medicine; Tumor microenvironment.

Fig. 1

Origin of glioblastoma. Abbreviations: NSCs: neural stem cell; GPCs: glial precursor cells; GBMCs: glioblastomas

Fig. 2

Key mutations of glioblastom. Abbreviations: TP53: tumor protein p53; PTEN: phosphatase and tensin homolog; EGFR: epidermal growth factor receptor; RB1: retinoblastoma gene 1

Fig. 3

Tumor microenvironment of glioblastoma. Abbreviations: GBM: glioblastoma; GSC: glioblastoma stem cell

Fig. 4

Tumor biology in glioblastoma: angiogenesis, invasion, hypoxia, and edema. Abbreviations: VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; HIF-1: hypoxia-inducible factor-1

Fig. 5

VEGF-mediated blood vessel formation and blood–brain barrier disruption in glioblastoma: implications for drug delivery. Abbreviations: BBB: blood–brain barrier; VEGF: vascular endothelial growth factor

Fig. 6

Clinical features of glioblastoma: early signs and neurological manifestations

Fig. 7

Molecular and phenotypic heterogeneity of glioblastoma: subtypes and origins. Abbreviations: NSCs: neural stem cells; GBM: glioblastoma

Fig. 8

Comprehensive classification of glioblastoma: molecular, histological, and prognostic insights. Abbreviations: GBM: glioblastoma; EGFR: epidermal growth factor receptor; PTEN: phosphatase and tensin homolog; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B-cells; CHI3L1: chitinase 3-like-1; MET: MET proto-oncogene, receptor tyrosine kinase; PDGFRA: platelet-derived growth factor receptor alpha; IDH: isocitrate dehydrogenase

Fig. 9

Advancements in glioblastoma therapy: from standard care to innovative strategies. Abbreviations: GBM: glioblastoma; TMZ: temozolomide; EGFR: epidermal growth factor receptor; IDH: isocitrate dehydrogenase; CAR-T: chimeric antigen receptor T-cell; CRISPR: clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; scRNA-seq: single-cell RNA sequencing

Fig. 10

Multimodal approaches in glioblastoma: enhancing outcomes through combination therapies. Abbreviations: GBM: glioblastoma; TMZ: temozolomide; MGMT: O6-methylguanine-DNA methyltransferase; PI3K: phosphoinositide 3-kinase; mTOR: mechanistic target of rapamycin; EGFR: epidermal growth factor receptor; Shh: Sonic hedgehog; GSIs: γ-secretase inhibitors; PD-1: programmed death-1; CTLA-4: cytotoxic T-lymphocyte antigen

Fig. 11

Biomarkers and precision medicine: unlocking insights into glioblastoma: diagnosis, prognosis, and treatment. Abbreviations: GBM: glioblastoma; IDH1: isocitrate dehydrogenase 1; MGMT: O6-methylguanine-DNA methyltransferase; EGFR: epidermal growth factor receptor; ATRX: alpha thalassemia/mental retardation syndrome X-linked; TP53: tumor protein P53; TERT: telomerase reverse transcriptase; VEGF: vascular endothelial growth factor; CDKN2A: cyclin-dependent kinase inhibitor 2A; p16INK4a: cyclin-dependent kinase inhibitor 2A, isoform p16; NF1: neurofibromin 1; MMP: matrix metalloproteinase; ECM: extracellular matrix; c-MET: MET proto-oncogene, receptor tyrosine kinase; S100B: S100 calcium binding protein B; CTCs: circulating tumor cells; EVs: extracellular vesicles; ctDNA: circulating tumor DNA; PD-L1: programmed death-ligand 1; miRNAs: MicroRNAs; circRNAs: circular RNAs