Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.

Glioblastoma (GBM) is an aggressive brain tumor characterized by molecular complexity and resistance to conventional treatments, including surgery, radiation, and chemotherapy. Despite these challenges, advancements in receptor tyrosine kinase (RTK) research, combined with multi-omics approaches, hold promise for improving patient outcomes and survivability. RTKs are central to GBM progression, influencing cell proliferation, survival, and angiogenesis. However, the complexity of RTK signaling necessitates a broader, integrative perspective, which has been enabled by the emergence of -omics sciences. Multi-omics technologies—including genomics, transcriptomics, proteomics, and metabolomics—offer unprecedented insights into the molecular landscape of GBM and its RTK-driven pathways. Genomic studies have revealed mutations and amplifications in RTK-related genes, while transcriptomics has uncovered alterations in gene expression patterns, providing a clearer picture of how these aberrations drive tumor behavior. Proteomics has further delineated changes in protein expression and post-translational modifications linked to RTK signaling, highlighting novel therapeutic targets. Metabolomics complements these findings by identifying RTK-associated metabolic reprogramming, such as shifts in glycolysis and lipid metabolism, which sustain tumor growth and therapy resistance. The integration of these multi-omics layers enables a comprehensive understanding of RTK biology in GBM. For example, studies have linked metabolic alterations with RTK activity, offering new biomarkers for tumor classification and therapeutic targeting. Additionally, single-cell transcriptomics has unveiled intratumoral heterogeneity, a critical factor in therapy resistance. This article highlights the transformative potential of multi-omics in unraveling the complexity of RTK signaling in GBM. By combining these approaches, researchers are paving the way for precision medicine strategies that may significantly enhance diagnostic accuracy and treatment efficacy, providing new hope for patients facing this devastating disease.

Glioblastoma (GBM) is an aggressive brain tumor characterized by its molecular complexity and resistance to conventional treatments, including surgery, radiation, and chemotherapy. Despite these challenges, advancements in receptor tyrosine kinase (RTK) research, combined with multi-omics approaches, hold promise for improving patient outcomes and survivability. RTKs, are central to GBM progression, influencing cell proliferation, survival, and angiogenesis. However, the complexity of RTK signaling necessitates a broader, integrative perspective, which has been enabled by the emergence of -omics sciences. Multi-omics technologies—including genomics, transcriptomics, proteomics, and metabolomics—offer unprecedented insights into the molecular landscape of GBM and its RTK-driven pathways. Genomic studies reveal mutations and amplifications in RTK-related genes, while transcriptomics uncovers alterations in gene expression patterns, providing a clearer picture of how these aberrations drive tumor behavior. Proteomics further delineates changes in protein expression and post-translational modifications linked to RTK signaling, highlighting novel therapeutic vulnerabilities. Metabolomics complements these findings by identifying RTK-associated metabolic reprogramming, such as shifts in glycolysis and lipid metabolism, which sustain tumor growth and therapy resistance. The integration of these multi-omics layers enables a comprehensive understanding of RTK biology in GBM. For example, studies have linked metabolic alterations with RTK activity, offering new biomarkers for tumor classification and therapeutic targeting. Additionally, single-cell transcriptomics has unveiled intratumoral heterogeneity, a critical factor in therapy resistance. This article highlights the transformative potential of multi-omics in unraveling the complexity of RTK signaling in GBM. By combining these approaches, researchers are paving the way for precision medicine strategies that may significantly enhance diagnostic accuracy and treatment efficacy, providing new hope for patients facing this devastating disease.

Adult astrocytomas, particularly IDH1/IDH2-wildtype infiltrating astrocytic gliomas, represent a significant challenge for medical professionals. Despite recent progress in understanding tumor biology and the use of molecular biomarkers, therapeutic options have not significantly improved patient outcomes. Although targeted therapies, such as small-molecule tyrosine kinase inhibitors (TKIs), have shown benefits in other solid tumors, they have largely failed to improve survival in adult astrocytoma patients. Characterized by remarkable heterogeneity, these tumors develop robust drug resistance mechanisms. The molecular processes driving this resistance are complex and not yet fully understood. In this review, we briefly present the growth factor receptors (GFRs) and their signaling pathways in adult astrocytomas and discuss the known mechanisms of resistance to small-molecule tyrosine kinase inhibitors.

Glioblastoma (GBM) shows extensive epigenetic heterogeneity. In IDH-wildtype (IDH-WT) GBM, promoter DNA methylation may regulate lineage programs influencing tumor evolution and prognosis; here, we systematically profiled promoter-level methylation dynamics across longitudinal tumors. Genome-wide DNA methylation data were obtained from the publicly available Gene Expression Omnibus (GEO; GSE279073) dataset, comprising a longitudinal cohort of 226 IDH-wildtype glioblastomas profiled on the Illumina Infinium EPIC 850K array across primary and recurrent stages at the University of California, San Francisco. From 333 Gene Ontology gliogenesis-annotated genes (GO:0042063), a 48-gene promoter panel was derived, with ≥2 probes per gene. Promoter methylation was summarized as the median β-value and tested using one-sample Wilcoxon with FDR correction. Functional enrichment, longitudinal variation, and patient-level methylation burden were assessed. Validation analyses were performed using independent IDH-wildtype GBM datasets from The Cancer Genome Atlas (RNA-seq and 450K methylation; n = 347). Promoter hypomethylation predominated across all stages, with 25 genes consistently hypomethylated and 7 hypermethylated. Functional enrichment highlighted gliogenesis, glial cell differentiation, neurogenesis, and Notch-related signaling. In TCGA, promoter methylation inversely correlated with expression for 11 of 33 genes (FDR < 0.05). An Expression Score contrasting hypomethylated and hypermethylated genes was positively associated with improved overall survival, where higher scores predicted better outcome (HR = 0.87, p = 0.016; Q4 vs. Q1 HR = 0.68, p = 0.025), and a complementary Methylation Score showed that higher promoter hypermethylation predicted poorer outcome (HR = 1.73, p < 0.001). CNTN2 and TSPAN2 were adverse prognostic genes (FDR < 0.05). The Expression Score was highest in Proneural tumors and lowest in Mesenchymal tumors (p < 0.001), reflecting a proneural-like state associated with better prognosis. Promoter methylation within gliogenesis genes defines a stable yet prognostically informative epigenetic signature in IDH-WT GBM. Hypomethylation promotes transcriptional activation and a favorable outcome, whereas hypermethylation represses lineage programs and predicts poorer survival.

Brain tumor (BT) patients can experience neurological complications as a result of the disease itself or after exposure to anticancer treatment. It is already known that BT patients have a poor survival and quality of life due to tumor progression, but also to various complications. The neurological complications may represent obstacles in patient management and require multidisciplinary collaboration. Although new methods of surgery, radiation therapy and pharmacotherapy have been designed in the last few years in order to prevent, mitigate, or manage the adverse effects of classical therapies, the overall survival of patients with BTs, especially glioblastoma (GB), remain poor. In this review we provide an overview of the most commo022328n neurological complications of BTs, as well as tumor therapies. We present what is already known on the topic but also the newest clinical data, and the results of clinical trials from the last few years. We also make a summary of the strategies capable of managing or even preventing these adverse effects.