Search Results (1,891)

Epigenetic dysregulation is a hallmark of glioblastoma (GBM) pathogenesis, with histone methylation playing a central role in chromatin remodeling and gene expression regulation. Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator responsible for histone methylation. It primarily functions as a transcriptional repressor and regulates signaling pathways associated with tumor progression. Importantly, EZH2 is frequently recruited to long non-coding RNA (lncRNA) scaffolds, including HOTAIR and AGAP2-AS1, thereby enabling coordinated gene silencing by establishing repressive chromatin states. Although EZH2 expression is not consistently associated with overall survival in GBM, EZH2 remains a promising therapeutic target due to its roles in stemness and treatment resistance. This review summarizes current knowledge of EZH2 functions in normal and GBM cells, highlighting its complex functions and therapeutic potential. We also discuss the current status and limitations of EZH2-targeting therapies, including challenges related to blood–brain barrier penetration and clinical translation. Although a combination of EZH2 inhibitors and other epigenetic inhibitors may be beneficial in selected molecular contexts, its rationale depends on the underlying regulatory network. Future therapeutic development will require biomarker-driven patient stratification and precision medicine approaches to maximize clinical benefit in GBM. Full article

Background/Objectives: RNA interference (RNAi) represents a promising therapeutic approach for silencing oncogenes involved in cancer progression by utilizing small interfering RNA (siRNA). However, siRNA requires an efficient delivery system to overcome cellular uptake and endosomal escape barriers. This study aimed to evaluate a multifunctional tandem peptide, GE11-599, designed to enhance the targeted delivery of siRNA and maintain its bioactivity in glioblastoma (GBM) cells. Methods: The GE11-599 peptide, consisting of an EGFR-targeting GE11 motif and a 599 fusogenic domain, was complexed with siRNA via electrostatic interactions to form nanoparticles. We assessed nanoparticle physicochemical properties, protection of siRNA from serum and RNase degradation, and cellular uptake in two GBM cell lines (U118MG and U87MG). Mechanistic studies evaluated receptor-mediated endocytosis and the subsequent escape from endosomes. Functional assays quantified STAT3 gene silencing and downstream effects on cell migration following treatment with GE11-599–siSTAT3 complexes. Results: GE11-599 formed positively charged, monodisperse nanoparticles capable of protecting siRNA from degradation. The tandem peptide significantly enhanced cellular internalization through EGFR-mediated endocytosis and facilitated endosomal escape of siRNA. Treatment with GE11-599–siSTAT3 resulted in robust gene silencing, achieving up to an 80% reduction in STAT3 mRNA expression. Downstream functional assessment showed a 40% decrease in migration in GBM cells treated with GE11-599–siSTAT3 complexes. Conclusions: The GE11-599 tandem peptide effectively enhances cell-specific internalization and endosomal escape of siRNA in GBM cells, resulting in increased siRNA bioactivity and functional gene silencing. These findings support GE11-599 as a promising siRNA delivery platform for targeting EGFR-expressing cancers. Full article

Background: Population-level patterns in the real-world use of initial treatment combinations for glioblastoma (GBM) remain poorly characterized. Materials and Methods: We assessed temporal trends in treatment and survival among patients with GBM in the SEER registry. Guideline-concordant multimodal therapy was defined as cancer-directed surgery combined with radiotherapy and chemotherapy. Outcomes were further stratified by extent of resection, including gross total resection (GTR) versus subtotal resection. Results: Among 46,186 patients, 43.5% underwent GTR, 32.0% subtotal resection, and 24.5% no surgery; 71.8% received radiotherapy and 61.3% received chemotherapy. From 2000 to 2020, utilization increased for any surgery (OR/year 1.03, 95% CI 1.028–1.036), radiotherapy (1.01, 1.010–1.017), and chemotherapy (1.08, 1.081–1.088), whereas the likelihood of GTR vs. subtotal resection declined (0.92, 0.915–0.922). Triple therapy increased modestly (1.01, 1.005–1.012) but plateaued at 30%. Older age, non-lobar tumors, unmarried status, and lower income predicted lower odds of triple therapy; after adjustment, calendar year showed a marginal decline in the odds of receiving triple therapy (aOR/year 0.99, 0.99–1.00). Median overall survival improved from 6.0 to 10.0 months, with gains in fixed-time survival. Patients receiving multimodal therapy demonstrated the longest survival overall; within this group, GTR-based multimodal therapy was associated with longer survival than subtotal resection-based multimodal therapy across age strata. Conclusions: Guideline-concordant multimodal therapy was associated with the longest survival. GTR rates did not rise in recent years, and substantial disparities in the deployment of GTR-based multimodal therapy persisted. Efforts to expand equitable access and prioritize maximal safe resection are essential to achieve greater population-level survival gains. These differences should be interpreted cautiously, as SEER cannot distinguish appropriate clinical treatment selection from limited access to care or treatment ineligibility. Full article

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood–brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling. Full article

Glioblastoma (GBM) recurs predominantly from infiltrative disease that persists beyond the contrast-enhancing tumor (CET). This structured narrative review aims to define the invasive margin and peritumoral brain zone (PBZ) as a spatially organized molecular ecosystem, summarize the approaches used to interrogate this compartment, and evaluate how malignant-cell plasticity, host niches, and treatment-induced remodeling contribute to minimal residual disease and recurrence. A structured literature search of PubMed/MEDLINE, Scopus, and Web of Science identified the clinical, translational, preclinical, and review literature available through July 2026; evidence was synthesized qualitatively, with priority given to human tissue studies and single-cell or spatially resolved analyses. Across studies, the margin differs from both tumor core and normal brain and contains heterogeneous malignant states interacting with neural, vascular, immune, hypoxic, and extracellular-matrix-supported niches. Surgery, radiotherapy, and systemic treatment further reshape these interactions through inflammation, vascular injury, senescence, hypoxia, and fibrosis. The main translational challenge is therefore not simply to control the CET, but to identify biologically high-risk non-enhancing tissue and demonstrate that therapy reaches and modifies it. We propose three priorities: image-registered characterization of residual compartments, regional measurement of drug exposure and target engagement, and integration of local margin control with distributed and niche-directed treatment. Prospective validation is required before spatial PBZ biomarkers can guide routine care. Full article

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. Full article

Background: Glioblastoma is a primary aggressive brain tumor, with an average survival rate of ~14.6 months. The low therapeutic benefit of current treatments is in part due to glioblastoma-initiating cells hijacking microglia/macrophages to support tumor growth, prompting the development of multitargeted therapeutic approaches. One such therapeutic target is transcription factor Nrf2. High Nrf2 activity is associated with high-grade tumors, and high Nrf2 levels in microglia/macrophages lead to polarization toward an immunosuppressive profile, supporting glioblastoma progression and therapy resistance. Interestingly, however, sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables and a potent Nrf2 activator, has anti-carcinogenic effects in multiple animal models. Methods: We utilized the zebrafish glioblastoma initiation model of human AKT1 overexpression in neuronal progenitors to capture the intermediate progenitor-cell-like state of glioblastoma-initiating/pre-neoplastic cells and evaluated the therapeutic potential of SFN and VVD130037, an Nrf2 inhibitor currently in clinical trials. Results: Initial findings suggest that SFN, individually and in combination with VVD130037, had the potential to decrease the levels of AKT1. Surprisingly, VVD130037 tended to increase AKT1. The pAKT1 levels also increased in Nrf2-deficient human cells. Moreover, failure to activate Nrf2 in neural progenitors in response to SFN, while a preliminary observation that warrants further investigation, suggests that the decrease in AKT1 was not potentially mediated by Nrf2 activation. The combined effect of SFN and VVD130037 on AKT1 was particularly strong in irf8-/- mutant larvae, which lack a microglia/macrophage population, indicating the existence of a non-tumorigenic cell population(s) sensitive to changes in Nrf2 activity. Conclusions: AKT1 inhibition in glioblastoma-initiating cells by the phytochemical SFN, combined with Nrf2 inhibition in the surrounding cells, may impede glioma progression. Full article

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions: DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy. Full article

Background/Objectives: The blood–brain barrier (BBB) remains a major obstacle to effective gene therapy for neurological disorders by limiting delivery of viral vectors, nanoparticles, and biologics to the central nervous system. Multiple strategies have been developed to transiently disrupt or bypass the BBB, including focused ultrasound (FUS) with microbubbles, osmotic agents, biochemical modulators, and receptor-mediated transport systems. Among these approaches, FUS-mediated BBB opening has emerged as the most spatially precise and clinically advanced strategy. Methods: This narrative review synthesizes recent preclinical and clinical literature on BBB microdisruption technologies for central nervous system gene therapy, with primary emphasis on FUS combined with microbubbles. We review BBB physiology, gene delivery platforms, the development of FUS technologies, optimization parameters, and translational evidence across neurological diseases from animal models through early-phase human studies. Results: FUS-mediated BBB opening has emerged as the leading method for transient barrier modulation. Preclinical studies in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, glioblastoma, amyotrophic lateral sclerosis, and lysosomal storage disorders demonstrate enhanced gene delivery, increased transgene expression, and improved functional outcomes. Large-animal studies and early clinical trials indicate that BBB opening is reversible, spatially controlled, and generally well tolerated. Clinical investigations have demonstrated successful delivery of therapeutic agents across neurological indications, with preliminary efficacy signals including improved drug penetration, metabolic changes, and potential survival benefits. Optimization of acoustic parameters, microbubble characteristics, and real-time cavitation monitoring remains critical for maximizing safety and therapeutic efficacy. Conclusions: BBB microdisruption, particularly through FUS with microbubbles, represents a transformative platform for central nervous system gene therapy. Continued research is needed to standardize treatment protocols, characterize long-term safety, and facilitate broader clinical translation. Full article

Background/Objectives: Bevacizumab is widely used at recurrence in glioblastoma, but comparisons are complicated by multimodal treatment selection and progression assessment. We examined outcomes associated with a bevacizumab-containing first-recurrence strategy and explored the components of post-recurrence progression-free survival (prPFS). Methods: This retrospective single-center cohort included 166 patients at first recurrence: 114 received a bevacizumab-containing strategy and 52 a non-bevacizumab strategy. Of these, 163 had evaluable outcomes. Local therapy at first recurrence was recorded in 19.3% and 90.4% of the groups, respectively. Treatment strategy was fixed at first recurrence to reduce immortal-time bias. Analyses used pretreatment covariates, multiple imputation, propensity-score overlap weighting, robust variance estimation, and competing-risk methods. Complete-case adjusted models included 117 patients. Recurrence-specific performance status, corticosteroid exposure, and MGMT status were unavailable. Results: Among 163 patients, 136 deaths and 145 prPFS events occurred. In the overlap-weighted analysis after multiple imputation, a bevacizumab-containing strategy was not associated with improved post-recurrence overall survival (OS; HR 1.40, 95% CI 0.93 to 2.10) or prPFS (HR 0.81, 95% CI 0.55 to 1.18). Competing-risk analysis showed a lower cause-specific hazard of documented second progression (HR 0.29, 95% CI 0.16 to 0.53) and a higher cause-specific hazard of death before documented progression, although its CI included the null (HR 1.65, 95% CI 0.93 to 2.93). Higher baseline neutrophil-to-lymphocyte ratio was associated with poorer OS (HR per doubling 1.49, 95% CI 1.20 to 1.85), but treatment interactions were inconsistent across parameterizations. Conclusions: A bevacizumab-containing first-recurrence strategy was not associated with improved post-recurrence OS or prPFS. Divergent progression and death patterns caution against interpreting progression-based endpoints as direct evidence of disease control in this observational setting. Full article

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM. Full article

Gliomas, and glioblastoma in particular, remain difficult to model because molecular heterogeneity, diffuse invasion, blood–brain and blood–tumour barrier effects, immune suppression and repeated therapeutic escape converge in the same disease. Two-dimensional cultures, glioma stem cell (GSC) systems, acute tumour slices and animal models remain indispensable for mechanistic research, pharmacology and in vivo validation. Glioma organoids are complementary research platforms, not components of routine diagnostic or treatment procedures. This review links model construction, microenvironmental validation, treatment perturbation and evidence-graded interpretation. We compare patient-derived glioma organoids, GSC-derived organoids, brain organoid–glioma co-cultures, genetically engineered brain tumour organoids, and vascular-associated, immune-cell-containing and chip-based platforms. We distinguish phenotypic resemblance from physiological fidelity, tumour-intrinsic drug sensitivity from delivery competence, and proof-of-concept activity from demonstrated clinical utility. We also examine temozolomide resistance, radiotherapy, targeted and combination therapy, antiangiogenic treatment, tumour-treating fields, immune-cell therapy, oncolytic viruses, multi-omic quality control and prospective validation. Organoids should not substitute for animal models or clinical trials. Their most defensible role is to provide a patient-derived functional layer between mechanism, regimen ranking and molecular tumour-board interpretation, with claims limited by assay reproducibility, clinically achievable exposure and outcome linkage. Full article

Background: Glioblastoma (GBM) carries a median survival of 15 months. Approximately 16–27% of patients die within six months despite standard therapy. Radiomic MRI features have been proposed as prognostic biomarkers, yet many published studies employ standard cross-validation (CV) with feature selection on the full dataset, introducing data leakage. Methods: Sixty patients with IDH-wildtype GBM from the publicly available UCSF-PDGM dataset (single-center, GE Discovery MR750, 3 T; 2015–2021) with BraTS 2021 segmentation masks were analyzed. One thousand two hundred eighty-four (1284) IBSI-compliant radiomic features (7 feature classes × 4 MRI sequences × 3 tumor subregions) were extracted using PyRadiomics. After preprocessing (variance filter, correlation filter |r| > 0.95), approximately 120 features remained per fold. Feature selection was performed strictly within each training fold of a nested 5-fold cross-validation framework (5-fold × 3 repeats = 15 outer folds). Results: For 1-year mortality, radiomics AUC dropped from 0.816 (standard CV) to 0.593 (nested CV; ΔAUC = −0.223, 27% inflation), while clinical models remained stable (0.708 vs. 0.705). For early mortality (≤180 days, n = 16 events), standard CV inflated radiomics AUC to 0.888, whereas nested CV yielded 0.815 (ΔAUC = −0.073, 8% inflation). In feature stability analysis, whole-tumor surface area (13/15 folds) and mesh volume (10/15 folds) showed the highest cross-endpoint stability; nine of 13 exploratory OS-associated features were never selected for early mortality classification. Extent of resection (HR = 0.44, p = 0.009) and age (HR = 1.03, p = 0.038) were independently associated with overall survival; tumor surface area remained independently associated with survival (HR = 1.38, p = 0.021). Conclusions: Nested cross-validation revealed substantial performance inflation in standard radiomics pipelines. These descriptive inflation estimates are specific to this dataset and pipeline configuration and should not be generalized as universal parameters for radiomics. Full article

This study reports the design, synthesis, and biological evaluation of novel inhibitors targeting the epigenetic enzymes ALKBH2 and ALKBH5 as potential adjuvants to temozolomide therapy in glioblastoma. Given their critical role in DNA/RNA demethylation, tumor progression, and drug resistance, their inhibition represents a promising therapeutic strategy. Building on the previously identified lead compound MV1035, we employed structure-based drug design to develop new derivatives, including a second-generation series incorporating a fumarate hydrazide moiety to enhance binding affinity through interaction with both substrate- and cofactor-binding sites. Molecular docking studies predicted significantly improved binding for a set of new compounds but, due to multiple synthetic drawbacks, only a subset of the designed series was synthesized and evaluated biologically. MV3030 emerged as the most promising candidate. MV3030 demonstrated an inhibitory effect on ALKBH2 comparable to MV1035, also showing a more moderate inhibitory effect on ALKBH5. Notably, it exhibited intrinsic cytotoxicity in U87-MG cells and patient-derived glioma stem cells, whereas normal astrocytes exhibited markedly higher resistance to the treatment. Furthermore, MV3030 enhanced temozolomide efficacy and displayed favorable blood–brain barrier permeability both in silico and in vitro. Moreover, MV3030 modulated the FoxM1/Wnt/β-catenin axis. Overall, these findings identify MV3030 as a promising compound with the potential to overcome temozolomide resistance and improve glioblastoma treatment. Full article

The urgent need for novel glioblastoma (GBM) therapies has motivated the exploration of EGFR G-quadruplex (G4) targeting, which suppresses oncogene transcription independently of kinase activity. However, existing EGFR G4 ligands lack subtype selectivity. Through computer-aided design and systematic bioisosteric modifications of the 1H-imidazo[4,5-f][1,10]phenanthroline scaffold, we synthesized a series of derivatives. We evaluated their G4 interactions by molecular docking, UV-Vis, FRET, ITC, and CD. Compound 3, bearing a 6-bromopiperonyl group, exhibited nanomolar affinity for EGFR G4 (Kd = 102 nM) with ~146-fold selectivity over K-Ras G4, stabilizing it via end-stacking. It potently inhibited U87-MG glioblastoma cell proliferation (IC₅₀ = 0.49 μM), with a wide safety margin relative to normal HMC3 microglia (safety index = 14.18). Mechanistically, compound 3 triggered DNA damage, mitochondrial oxidative stress, and sequential multi-organelle damage to mitochondria, lysosomes, and the endoplasmic reticulum, while impairing cell migration and invasion. These findings establish compound 3 as a uniquely selective EGFR G4 stabilizer, offering a promising multi-organelle-damage strategy for glioblastoma therapy. Full article