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PubMed2025

Circadian variation in MGMT promoter methylation and expression predicts sensitivity to temozolomide in glioblastoma.

PURPOSE: Recent studies show that glioblastoma (GBM) is more sensitive to temozolomide (TMZ) in the morning. In cells, inhibiting O6-Methylguanine-DNA-Methyltransferase (MGMT) abolished time-dependent TMZ efficacy, suggesting that circadian regulation of this DNA repair enzyme underlies daily TMZ sensitivity. Here, we tested the hypotheses that MGMT promoter methylation and protein abundance vary with time-of-day in GBM, resulting in daily rhythms in TMZ efficacy. METHODS: We assessed daily rhythms in MGMT promoter methylation in GBM in vitro and retrospectively analyzed MGMT methylation status in human GBM biopsies collected at different times of day. Next, we measured MGMT and BMAL1 protein abundances in GBM cells collected at four-hour intervals. To understand the therapeutic implications of circadian variations in MGMT, we incorporated its daily rhythms into an in vitro mathematical model capturing interactions between MGMT, TMZ, and GBM DNA. RESULTS: We found daily rhythms in MGMT promoter methylation and protein levels in GBM in vitro, and in patient biopsies peaking at midday. Further, MGMT protein levels peaked at CT4, corresponding to the time of maximal TMZ efficacy in vitro. When we incorporated cell-intrinsic circadian rhythms in MGMT protein into a mathematical model for GBM chemotherapy, we found that dosing when daily MGMT levels peaked and began to decline produced maximum DNA damage. CONCLUSION: Our findings suggest that the likelihood of diagnosis of MGMT promoter methylation may vary with time of biopsy in GBM. Furthermore, theoretical modeling predicts that efforts to deliver TMZ after the daily peak of MGMT activity, with exact time being dose-dependent, may significantly enhance its therapeutic efficacy.

Humans↗
PubMed2026

Extracellular Vesicles From Glioblastoma Cells Reflect 2D vs. 3D Culture Adaptation and Resistance to Temozolomide.

Glioblastoma (GBM) is an aggressive brain tumor marked by extensive heterogeneity, resistance to therapy, and dismal prognosis. Extracellular vesicles (EVs) have emerged as key players in GBM biology, mediating intercellular communication and therapy adaptation. However, the exact functions and molecular impact of EVs in GBM remain incompletely understood. In this study, we performed a comparative proteomic analysis of U87MG GBM cells grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroids following temozolomide (TMZ) treatment, alongside characterization of EVs derived from both culture systems. 3D-spheroids secreted more EVs of smaller size and exhibited a more TMZ-resistant, stem-like proteome under TMZ-induced genotoxic stress. In contrast, 2D cell cultures demonstrated greater proteome remodeling, with EVs enriched in protein families involved in DNA repair, oxidative stress adaptation, and methylation processes. Notably, several methyltransferases were decreased intracellularly but selectively retained in EVs, suggesting active sorting to influence the tumor microenvironment or modulate epigenetic states in recipient cells. EVs also carried adhesion molecules and signaling proteins linked to migration, invasion, and Wnt pathway activation, as well as metabolic enzymes connecting serine metabolism and redox control to TMZ resistance. Mapping EV and cellular proteomes onto The Cancer Genome Atlas (TCGA) dataset identified prognostic protein families associated with either poor or favorable patient outcomes. Our data demonstrate that EV cargo composition mirrors TMZ-induced phenotypic adaptation and reveals molecular mechanisms underlying therapeutic resistance. These EV-associated signatures may serve as clinically actionable biomarkers for patient stratification and offer potential targets to overcome chemoresistance in GBM.

Humans↗
PubMed2026

ABCB1 Polymorphisms Influence on Temozolomide Resistance and Overall Survival in Glioblastoma Patients: A Systematic Review of Clinical Evidence.

Glioblastoma (GB), defined as IDH-wildtype CNS WHO grade 4 tumour according to the 2021 WHO classification of CNS tumours, remains a uniformly lethal malignancy in which the efficacy of temozolomide (TMZ) continues to be constrained by both intrinsic tumur biology and the pharmacological barrier imposed by the blood-brain barrier (BBB). Given the central role of the ABCB1 (MDR1/P-glycoprotein) efflux transporter in regulating CNS drug disposition, germline variation in ABCB1 has been proposed as a potential determinant of interindividual variability in TMZ response. This systematic review synthesised clinical evidence from four independent studies, encompassing more than 400 GB patients, evaluating the association between ABCB1 polymorphisms and TMZ efficacy and patients' survival. Across the available literature, the influence of ABCB1 genetic variation emerged as limited and inconsistent. An early study reported a marked survival advantage for carriers of the ABCB1 C1236T C/C genotype treated with TMZ, suggesting reduced efflux and enhanced drug exposure. However, subsequent investigations, including epigenetic analyses, high-quality multivariate survival modelling and a pharmacokinetic study demonstrating genotype-dependent differences in plasma TMZ concentrations, did not replicate a corresponding survival effect. Across the remaining cohorts, common variants such as 1236C>T, 2677G>T/A, 3435C>T and 1199G>A showed no robust association with clinical outcome, indicating that transporter-mediated modulation is likely overshadowed by dominant prognostic drivers, including MGMT methylation, IDH status and tumour heterogeneity. Collectively, current evidence does not support ABCB1 polymorphisms as reliable predictive biomarkers of TMZ response in GB. Nonetheless, the pharmacokinetic signals observed, together with emerging technologies capable of selectively modulating efflux activity at the tumour-BBB interface, point to a continued role for ABCB1 in future therapeutic strategies. Integration of transporter genomics with spatial pharmacokinetics and molecular stratification will be essential to refine drug delivery and improve outcomes in GB.

Humans↗
PubMed2026

ERP44 Is Associated With Poor Prognosis and Promotes Proliferation and Temozolomide Resistance in Lower-grade Glioma.

BACKGROUND/AIM: Endoplasmic reticulum resident protein 44 (ERP44), a protein disulfide isomerase family member, has been implicated in tumor biology, but its role in lower-grade glioma (LGG) remains unclear. This study investigated the prognostic significance and biological function of ERP44 in LGG, focusing on proliferation and temozolomide (TMZ) resistance. MATERIALS AND METHODS: ERP44 expression, clinicopathological associations, and prognostic value were analyzed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets. Time-dependent receiver operating characteristic (ROC) curves, Cox regression, and a prognostic nomogram were constructed. Differential expression, Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) enrichment, immune infiltration, and drug sensitivity analyses were performed. Functional validation was conducted in SW1088 and SW1783 cells using shRNA-mediated ERP44 knockdown, followed by RT-qPCR, western blotting, CCK-8, colony formation, and TMZ IC50 assays. Subcutaneous xenograft models with or without TMZ treatment were used for in vivo validation. RESULTS: ERP44 was markedly upregulated in LGG and associated with higher WHO grade, IDH wildtype status, 1p/19q non-codeletion, and poor survival in TCGA and CGGA cohorts. ERP44 showed strong prognostic performance and improved risk stratification in a multivariable nomogram. Enrichment analyses linked high ERP44 expression to immune/inflammatory pathways and reduced neuronal functional signatures. ERP44 positively correlated with immune infiltration, proliferation/stemness markers, and predicted TMZ resistance, while its knockdown inhibited proliferation and colony formation, reduced TMZ IC50, suppressed xenograft growth, enhanced TMZ efficacy, and decreased Ki67 positivity. CONCLUSION: ERP44 is a prognostic biomarker that promotes LGG proliferation and TMZ resistance, suggesting its potential as a therapeutic target.

Humans↗