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PubMed2025

NR2F6 regulates Temozolomide resistance in glioma via the E2F2-PARP1 pathway.

BACKGROUND: Glioma is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Elucidating the mechanisms of temozolomide (TMZ) resistance in glioma is of critical clinical importance for improving patient prognosis and developing novel therapeutic strategies. METHODS: We obtained RNA sequencing (RNA-seq) data of 648 glioma samples from The Cancer Genome Atlas (TCGA) and 325 samples from the Chinese Glioma Genome Atlas (CGGA) as study cohorts. Additionally, we validated the expression characteristics of the NR2F6 gene in our in-house cohort of glioma patients. Furthermore, we investigated the potential mechanism of NR2F6 in TMZ resistance in glioma by constructing TMZ-resistant cell lines in vitro. Statistical analyses and graphical work were primarily performed using R language and GraphPad Prism software. RESULTS: We observed a significant upregulation of NR2F6 expression in high-grade gliomas, which is associated with an unfavorable prognosis in patients. Concurrently, our findings revealed a significant upregulation of NR2F6 in drug-resistant cells, which induced TMZ resistance in glioma cells via the E2F2-PARP1 axis. CONCLUSION: In brief, NR2F6, as a nuclear transcription factor, enhances the transcription of E2F2.The increased expression of E2F2 enhances PARP1 expression, which in turn facilitates TMZ-mediated DNA damage repair, thereby diminishing glioma sensitivity to TMZ.

Journal Article↗

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↗

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

Clinical relevance of HRD score in pheochromocytomas and paragangliomas: molecular cluster distribution and prognostic implications.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential across molecular clusters. While the homologous recombination deficiency (HRD) score has been established as a surrogate for HRD-related genomic instability to guide prognostic evaluation and therapeutic options in multiple solid tumors, its relevance in PPGLs remains unexplored. Here, data from 133 PPGL patients in the TCGA database were extracted to assess relationships between the HRD score and molecular clusters, metastasis, metastasis-free survival (MFS), and other clinical characteristics. Subsequently, a real-world cohort of 54 matched blood-tumor pairs was subjected to whole-exome sequencing, with HRD scores calculated to confirm the prior observations. The median HRD score was 7.0 and 9.0 in the TCGA-PPGL dataset and the clinical cohort, respectively. In the TCGA dataset, an elevated HRD score significantly correlated with metanephrine secretion, C2 cluster, and metastasis. Multivariate analysis identified a higher HRD score as an independent risk factor for shorter MFS (HR = 1.33, P = 0.008). Patients with HRD scores ≥ 7 exhibited significantly shorter MFS (P = 0.037), which was observed exclusively within the C1A cluster (P = 0.007). Analyses of our clinical validation cohort corroborated this cluster-specific distribution and further revealed higher HRD scores in three temozolomide-treated PPGLs compared with those treatment-naive C1A tumors (P = 0.043). In conclusion, despite exhibiting lower levels in C1A clusters, an elevated HRD score emerges as a promising indicator for refined metastatic risk stratification in PPGLs. Futhermore, the substantial increase in HRD score following temozolomide treatment provides a rationale for PARP inhibitor sequential or combination therapy in metastatic PPGLs.

Humans↗

PubMed2026

Radiomics-based gradient boosting model on contrast-enhanced MRI for non-invasive prediction of epidermal growth factor receptor expression and therapeutic response to EGFR-targeted antibody-drug conjugates in high-grade glioma organoid models.

BACKGROUND: Epidermal growth factor (EGF) and its receptor EGF(EGFR) play crucial roles in glioblastoma (GBM) prognosis. However, non-invasive assessment of their expression remains challenging. This study aimed to determine whether radiomics features extracted from contrast-enhanced MRI could predict EGFR expression in high-grade gliomas (HGG) and to explore their associations with immune infiltration and therapeutic response of EGFR-Targeted antibody drug conjugates(EGFR-ADCs). METHODS: We extracted radiomic features from contrast-enhanced MRI of 298 GBM patients from The Cancer Imaging Archive (TCIA) and matched them with RNA-seq data from The Cancer Genome Atlas (TCGA). Feature selection was performed using minimum redundancy maximum relevance (mRMR) and recursive feature elimination (RFE). Machine learning models were built to predict EGF/EGFR expression. Radiogenomic associations were validated by immune infiltration analysis. Patient-Derived Tumor-Like Cell Clusters (PTC) were used to compare the antitumor efficacy of EGFR- ADCs and temozolomide. RESULTS: Elevated EGF/EGFR expression correlated with poor prognosis and increased infiltration of M2 macrophages, regulatory T cells, and CD4⁺ memory T cells. Pathway analysis demonstrated significant enrichment of the mechanistic target of rapamycin (mTOR) and Mitogen-Activated Protein Kinase (MAPK) signaling cascades. Radiomics-based prediction models achieved robust performance (AUC > 0.85) in stratifying EGFR expression status. In EGFR-positive tumor tissues, EGFR-ADCs exerted antitumor efficacy similar to that of temozolomide. CONCLUSIONS: EGF/EGFR expression is associated with immunosuppressive microenvironments and adverse outcomes in HGG. Radiomics may provide a non-invasive approach for estimating EGFR expression, although model performance requires external validation and EGFR-ADCs showed partial inhibitory activity within the tested range, though potency remains to be defined.These findings suggest a framework into radiogenomic stratification and targeted therapy in GBM.

Radiomics↗

PubMed2026

Mutational signature stratification of recurrent gliomas reveals distinct patterns of genomic traits.

BACKGROUND: Although temozolomide (TMZ) is widely used for glioma treatment, its therapeutic benefit is limited by acquired resistance and recurrence, facilitated by intratumor heterogeneity. Mutational signatures (MSs) inform tumor evolution and reveal alterations associated with treatment response. METHODS: We performed molecular analyses of 96 glioma recurrences with sufficient private single-nucleotide variants relative to their matched primary tumors, stratified by their dominant MS. RESULTS: Four groups were identified: MS11/TMZ-related (n = 38), MS1/5/aging-related (n = 32), MS6/15/21/26/microsatellite instability (MSI)-related (n = 13), and other MS-related recurrences (n = 13). MS11/TMZ-related recurrences showed higher acquired mutational counts than the other groups (1338 vs 59 (MS1/5/aging) vs 57 (MS6/15/21/26/MSI) vs 57 (other MSs); P < .01). Mutations in SYNE2, SZT2, and FBN3 were restricted to recurrences with dominant or second-dominant MS11/TMZ-related signature (n = 41), and 85% (35/41) harbored mutations in these genes. In MS11/TMZ-related recurrences with RNA sequencing data (n = 17), mRNA co-expression analyses identified SYNE2-ATAD5 and SZT2-MAPKBP1 associations. Among MS11/TMZ-related recurrences, MS23 was frequent (44%, 18/41) and associated with higher acquired mutational counts (2089 vs 1188; P = .018) and more IDH-wildtype tumors (67% vs 30%; P = .037). MAPKBP1 mutations were enriched in MS23-positive recurrences (56% (10/18) vs 0% (0/23); P < .001). MS1/5/aging-related recurrences showed more frequent acquired chromosome 16q losses (22% vs 8% (TMZ) vs 0% (MSI) vs 0% (other); P < .05), which were associated with an increased fraction of genome altered relative to 16q-diploid cases (15% vs 7%; P = .01). CONCLUSIONS: These findings show that MS-based stratification of recurrences refines molecular characterization after therapy and nominates candidate biomarkers and pathways for functional studies of treatment-associated glioma evolution.

mutational signatures↗

PubMed2026

Spatial Omics in High-Grade Gliomas: Mapping Immune-Tumor Niches for Precision Therapy.

High-grade gliomas (HGGs), particularly glioblastoma (GBM), remain among the most lethal human cancers despite decades of molecular profiling and therapeutic innovation. A primary reason for treatment failure is that HGG biology is spatial: malignant cell states, immune suppression, metabolic stress, and therapeutic resistance are organized into distinct anatomical and functional niches. Spatial omics technologies now enable high-dimensional mapping of gene expression, protein signaling, immune architecture, and metabolic activity within intact tumor tissue. These approaches reveal how proneural and mesenchymal transcriptional states coexist yet localize to distinct regions, alongside hypoxic, invasive, and stem-enriched niches. Spatial analyses show that key clinical determinants, including O6-methylguanine-DNA methyltransferase (MGMT)-associated temozolomide resistance, radiotherapy tolerance in hypoxic regions, and immunotherapy failure driven by myeloid-dominated immune exclusion, are influenced not only by molecular programs but also by cellular location. Beyond biological insight, spatial omics is reshaping clinical paradigms by enabling region-specific patient stratification, early assessment of treatment response, and identification of therapy-resistant reservoirs that seed recurrence. Prior bulk and single-cell studies defined HGG cell states and pathways but often treated resistance as tumor-wide. This review presents a spatially explicit framework that synthesizes spatial transcriptomic and immune-profiling studies to identify tumor-immune niches and spatial bottlenecks that drive therapeutic failure and recurrence.

Humans↗

PubMed2026

Vimentin loss inhibits DNA damage responses and promotes cancer cell survival.

Vimentin intermediate filaments are a hallmark of aggressive tumours and are widely linked to invasion and EMT, yet how vimentin-dependent mechanics shape genome maintenance and therapy response is unclear. Here we show that vimentin, particularly under compressive load, promotes DNA repair competence. In contrast, vimentin-negative cells show impaired DNA damage sensing and downstream signaling, ultimately leading to decreased apoptosis and promoting cell survival under genotoxic stress at the expense of genomic stability. Using controlled cell compression together with genetic and pharmacological perturbations, we find that loss of vimentin in glioblastoma cells limits the expression and activity of core repair pathways because of induced nuclear mechanical compression. Relieving nuclear compression restores DNA damage accumulation and repair kinetics. Functionally, suppression of DNA damage responses enhances survival after clinically relevant DNA-damaging treatments, including temozolomide, X-Ray radiation and cell invasion through tight spaces. These findings invert the prevailing view that vimentin's contribution to tumour progression stems from enhanced migration and identify a mechanochemical vimentin-nucleus axis that tunes DNA damage responses to favor therapy tolerance and genome evolution.

Journal Article↗

PubMed2026

Fluorescent reporter assay reveals ribonucleotides promote mismatch correction in vivo.

Ribonucleotides can serve as a strand discrimination signal in reconstituted in vitro biochemical mismatch repair (MMR) assays, but the influence of ribonucleotides on mismatch correction has not been measured directly in vivo. We have developed a fluorescence-based host cell reactivation assay that reports correction of a mismatch in proximity of a site-specifically incorporated ribonucleotide. A ribonucleotide leads to enhanced mismatch correction. While neither inactivation of a single allele nor knockdown of RNaseH2 is sufficient to suppress ribonucleotide directed MMR, a modest but statistically significant impairment for repair of mismatches in the presence of an embedded ribonucleotide is observed in RNaseH2 knockout cell lines. Reporter plasmids with ribonucleotides located in either the 3' or 5' orientation are robustly repaired in MMR-proficient cells but are weakly repaired in MMR-deficient cells, underscoring their utility as effective MMR reporters. Significant ribonucleotide-enhanced mismatch correction was consistently observed in MMR-deficient cells when the ribonucleotide is in the 3' orientation. The presence of a ribonucleotide led to enhanced MMR even in RNaseH2 knockout cells, suggesting that other enzymes may promote ribonucleotide-directed MMR. Loss of RNaseH2 was not sufficient to confer significant resistance to the alkylating agent, temozolomide, in support of a model in which ribonucleotide-directed repair events make minor contributions to the canonical MMR pathway in mammalian cells. We propose a model in which MMR-independent ribonucleotide enhanced correction of mismatches can proceed by ribonucleotide excision repair when the ribonucleotide is in the 5' direction, and proceeds by an unknown mechanism when the ribonucleotide is in the 3' direction.

DNA Mismatch Repair↗

PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗

PubMed2025

Infectious bursal disease virus (IBDV) as a novel oncolytic virotherapy in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive form of cancer of the central nervous system. Despite advances in immunotherapies and standard-of-care treatments for GBMs, clinical outcomes remain limited-owing to the immunosuppressive tumor microenvironment and the intrinsic resistance of GBM to conventional approaches. As a result, there is growing interest in rational combination strategies, particularly those pairing oncolytic viruses with immune-based therapies or established treatment modalities. Oncolytic viruses, by displaying conditionally enabled tumor cell-restricted replication, while stimulating antitumor immune responses and leaving healthy tissue unharmed, have the potential to reshape the therapeutic landscape in GBM and aid in achieving more durable benefits for patients. This study investigates the use of infectious bursal disease virus (IBDV) as a potential virotherapy for GBM. METHODS AND RESULTS: In vitro, IBDV infects and replicates within murine GBM cells and patient-derived GBM stem cells, inducing direct oncolysis and activating proinflammatory gene expression programs. IBDV also enhances the cytolytic activity of temozolomide (TMZ) in treated GBM cells, complementing TMZ chemotherapeutic activity. In vivo, treatment with IBDV in CT-2A GBM-bearing syngeneic mice significantly reduced tumor growth and improved survival compared with control mice. Intratumoral administration of IBDV induces a deep remodeling of the tumor immune microenvironment, reducing immunosuppressive M2-like macrophages and increasing the ratio of CD8+T cells to regulatory T cells. This reversion of immunosuppression linked to monocyte-derived macrophages has been confirmed on experimental ex vivo infections of explants derived from human GBM donors. CONCLUSION: These findings support further consideration of IBDV as a novel virotherapeutic agent for GBM.

Oncolytic Virotherapy↗

PubMed2026

First-in-Class Small Molecule Inhibitor of Oncogene AVIL in Glioblastoma.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant primary brain tumor, marked by rapid growth, extensive invasiveness, and a median survival of only ∼15 months despite current multimodal therapy. To identify new therapeutic vulnerabilities, we investigated the actin-regulatory protein AVIL, previously implicated through a MARS-AVIL gene fusion in rhabdomyosarcoma. Comprehensive genomic and transcriptomic analyses across REMBRANDT, TCGA, and CGGA datasets revealed recurrent AVIL amplification and consistently elevated AVIL expression in GBM compared with normal brain tissue. AVIL was overexpressed across all GBM molecular subtypes and glioma stem cell (GSC) states but was nearly undetectable in normal astrocytes, neural stem cells, and brain tissues. Functional studies demonstrated that AVIL is both necessary and sufficient for glioma genesis: AVIL silencing eradicated GBM cells in vitro and suppressed xenograft growth in vivo, while AVIL overexpression enhanced proliferation, migration, and transformation. Mechanistically, AVIL drives tumor progression through actin cytoskeleton remodeling and activation of the FOXM1-LIN28B oncogenic pathway. Using a small molecule microarray screen, we identified a selective AVIL-binding compound (compound A) that potently inhibited GBM cell growth with minimal toxicity to normal astrocytes. Gene expression changes induced by compound A mirrored those following AVIL knockdown, indicating on-target activity. Compound A demonstrated robust antitumor efficacy in multiple preclinical GBM models, including orthotopic xenografts, GSC-derived tumors, patient-derived xenografts, and temozolomide-resistant GBM with favorable pharmacokinetics and blood-brain barrier penetration. The minimal AVIL expression in normal tissues and lack of phenotype in AVIL-deficient mice underscore its potential as a low-toxicity therapeutic target. Together, these findings establish AVIL as a critical oncogenic driver in GBM and introduce a first-in-class AVIL inhibitor with strong translational promise for precision neuro-oncology.

Glioblastoma↗

PubMed2026

Integrating Radiogenomics and CSF-Based Liquid Biopsy Sequencing for Precision Neuro-Oncology.

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.

Humans↗

PubMed2025

Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy.

Tumor organoids are important tools for cancer research, but current models have drawbacks that limit their applications for predicting response to therapy. Here, we developed a fast, efficient, and complex culture system (IPTO, individualized patient tumor organoid) that accurately recapitulates the cellular and molecular pathology of human brain tumors. Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric, and metastatic brain cancers. Histopathological, genomic, epigenomic, and single-cell RNA sequencing (scRNA-seq) analyses demonstrated that the IPTO model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized cancer therapy.

Humans↗