Search Results (154)

Nimotuzumab is a humanized anti-EGFR monoclonal antibody with a unique pharmacodynamic profile characterized by intermediate affinity and bivalent binding dependence, enabling density-selective tumor targeting while sparing normal tissues from the severe skin rash and other toxicities common to EGFR inhibitors. Since its first approval in 2002, nimotuzumab has been registered for eight cancer indications. Unlike conventional fixed-dose schedules, emerging evidence supports prolonged administration beyond initial combination therapy. This review summarizes clinical data from pancreatic cancer, esophageal cancer, high-grade glioma, pediatric diffuse intrinsic pontine glioma, head and neck squamous cell carcinoma, nasopharyngeal cancer and other solid tumors, showing that extended nimotuzumab exposure, often as maintenance monotherapy, may prolong overall survival, progression-free survival, and disease control compared to limited cycles. Despite heterogeneity in tumor types and treatment regimens, maintenance nimotuzumab was consistently associated with better results, particularly in terms of overall survival. Notably, significant survival benefits were observed in locally advanced SCCHN (24.9 vs. 12.5 months) and esophageal cancer (15.9 vs. 8.1 months) across independent clinical trials. Mechanistically, nimotuzumab exerts direct cytostatic effects via G1 arrest, potent anti-angiogenic activity through VEGF downregulation, indirect pro-apoptotic effects, and broad immunomodulation including ADCC, NK-DC cross-talk, EGFR-specific CD8+ T cell priming, upregulation of HLA class I, and favorable regulation of regulatory T cells. Its density-selective binding reduces selective pressure for acquired resistance. Future research priorities should include prospective randomized trials specifically evaluating maintenance strategies, biomarker-driven patient selection, the molecular characterization of resistance mechanisms, integration with immunotherapy and modern combination regimens, and the development of next-generation platforms, including antibody–drug conjugates and multi-specific constructs. Full article

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background/Objectives: Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant malignancies, driven in part by heterogeneous, therapy-resistant glioma stem cells (GSCs). Improving clinical outcomes will require innovative therapeutic approaches that target unique molecular vulnerabilities. The mitogen-activated protein kinase (MAPK) pathway drives tumor progression across multiple cancers, including GBM. MAPK-interacting kinases (MNK1/2) represent MAPK downstream effectors that phosphorylate eukaryotic translation initiation factor 4E (eIF4E), a regulator of oncogenic and anti-apoptotic mRNA translation. We previously identified pharmacological MNK inhibition as a promising therapeutic strategy for GBM, but most available MNK inhibitors lack specificity. Methods: Novel MNK inhibitor compounds were developed using medicinal chemistry optimization and evaluated through molecular docking and kinome profiling analyses. Antineoplastic activity was assessed in established GBM cell lines and patient-derived glioma stem cell models cultured as 3-D neurospheres under stem cell-permissive conditions. Effects on MNK signaling, cell viability, neurosphere growth, migration, invasion, and apoptosis were analyzed using immunoblotting, flow cytometry, viability assays, wound healing assays, and 3-D invasion assays. In addition, a compound screen was performed to identify therapeutic agents that enhance MNK-targeted therapy, followed by validation using pharmacological inhibition and siRNA-mediated knockdown approaches. Results: Our next-generation MNK inhibitor NUCC-201893 exhibited high target specificity and greater potency than the lead compound NU808, effectively suppressing eIF4E phosphorylation, GBM cell viability, neurosphere growth, migration, and invasion. Compound screening identified DNA methyltransferase (DNMT) inhibition as a potent enhancer of MNK blockade. Pharmacological DNMT inhibition enhanced the cytotoxic effects of siRNA-mediated MNK1 knockdown, while concurrent pharmacological inhibition of MNKs and DNMT resulted in greater suppression of neurosphere growth and robust induction of apoptotic responses in GSCs. Conclusions: These findings identify dual MNK and DNMT inhibition as a promising combinatorial strategy that effectively triggers antineoplastic effects in GBM cells and GSCs. Full article

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its derived active ingredients and herbal formulations, with its advantages of multi-component, multi-target, and holistic regulation, demonstrates significant potential in the comprehensive treatment of this disease. This review systematically outlines the research progress in TCM for combating glioma. Regarding mechanisms of action, active TCM components not only directly inhibit tumors by inducing cell apoptosis but also exert synergistic therapeutic effects via multiple pathways. These include remodeling the immunosuppressive microenvironment, activating novel cell death programs such as ferroptosis and immunogenic cell death, intervening in tumor metabolic reprogramming, and reversing chemotherapy resistance. In terms of overcoming delivery barriers, drug delivery systems represented by nanocarriers, liposomes, and extracellular vesicles, combined with the penetration-enhancing effects of aromatic orifice-opening herbs (a class of TCM medicinals traditionally used to “open the orifices” and awaken the mind, now recognized to transiently enhance BBB permeability), have significantly improved the brain-targeting efficiency and bioavailability of TCM components. For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine. Full article

Background: High-grade glioma (HGG), formerly known as Glioblastoma multiforme, can be complicated by hematomas, either at the initial presentation or after surgical removal. Rarely, postoperative bleeding can occur extra-axially, resulting in subdural hematomas (SDH) that might require surgical evacuation. Of note, little is known about the cellular composition of those hematomas. Observations: We present the case of a patient operated on for HGG who developed postoperative recurrent SDH that required multiple surgical evacuations. Histopathological analyses of the membranes comprising the SDH revealed the presence of HGG tumoral cells. Conclusions: Based on our observation, hematomas associated with HGG, either extra or intra-axial, should be suspected of being a sign of tumoral recurrence or spread and histopathological analyses might be considered as they could lead to further adaptation of the patient’s treatment. Full article

Lower-grade gliomas (LGGs) often follow a relatively protracted clinical course; however, a substantial proportion eventually undergo malignant transformation to high-grade, treatment-refractory disease. This process has traditionally been interpreted in the context of stepwise histopathologic progression and recurrent genetic alterations. Increasing evidence, however, suggests that malignant transformation is more accurately understood as an evolutionary process shaped by the interplay among epigenetic constraints, cell-state plasticity, and selective pressures. In this review, we examine current evidence supporting a model in which early LGGs, particularly isocitrate dehydrogenase (IDH)-mutant tumors, are initially maintained in relatively restricted cellular states by metabolically imposed epigenetic programs, but progressively escape these constraints under the cumulative influence of therapy, hypoxia, immune remodeling, and genomic instability. We summarize recent advances demonstrating that progression from lower-grade to high-grade disease is accompanied by cell-state transitions characterized by altered lineage identity, acquisition of stem-like features, increased proliferative capacity, and adaptation to cellular stress. We further discuss how these transitions are reinforced by microenvironmental evolution, including vascular remodeling, extracellular matrix reorganization, and changes in immune composition, thereby creating conditions that favor clonal expansion, invasion, and therapeutic resistance. Particular attention is given to longitudinal, single-cell, and spatially resolved studies, which collectively indicate that malignant transformation is not a discrete event but a continuous process of evolutionary selection and phenotypic reprogramming. Finally, we discuss the translational implications of this framework for early risk stratification, biomarker development, and mechanism-based therapeutic intervention. By reframing malignant transformation in LGGs as a process of cell-state escape under persistent selective pressure, this review aims to provide an integrated view of glioma progression and to highlight new opportunities for precision monitoring and treatment. Full article

Diffuse midline gliomas (DMGs) are rare but highly aggressive central nervous system (CNS) tumors that can present in both pediatric and adult populations. These tumors were redefined in the 2016 WHO classification of CNS tumors based on integrated histopathological and molecular features, and were initially designated as “DMG, H3 K27M-mutant”. In the 2021 WHO update, DMGs were incorporated into the newly defined category of primarily pediatric-type diffuse high-grade gliomas, and nomenclature was changed to “DMG, H3 K27-altered” to encompass additional molecular drivers beyond the canonical H3 K27M mutation. Clinically, DMGs arise as expansile, infiltrating tumors within midline structures and may present as non-enhancing or enhancing lesions on imaging. Diagnosis is based on neuroimaging and molecular confirmation by immunohistochemistry or sequencing when tissue is available. DMGs are categorized as WHO grade 4 malignant tumors due to their aggressive biology leading to rapid and infiltrative growth. Owing to their deep and midline location, surgical resection is typically not feasible. Radiation therapy is the backbone of treatment, but there is no standard regimen of chemotherapy that has demonstrated durable efficacy. Recent progress in therapeutic approaches has led to a major breakthrough on 6 August 2025 when the U.S. Food and Drug Administration granted the accelerated approval of dordaviprone (ONC201), marking it as the first systemic therapy for progressive DMG harboring H3 K27M mutation. Other novel approaches, including chimeric antigen receptor (CAR) T-cell directed therapies and convection-enhanced delivery, are actively under investigation. We aim to comprehensively review DMGs, including the recent insights into their biology, the evolving therapeutic landscape, and the opportunities to fuel this new momentum against one of the most formidable gliomas. Full article

Background/Objectives: Glioblastoma remains the most lethal primary brain tumor in adults, and progress in oncolytic virotherapy is limited by the lack of immunocompetent models permissive to human-tropic viruses. Methods: Here, murine CT-2A and GL261 glioma and B16 melanoma cell lines were engineered to express human Coxsackievirus and Adenovirus Receptor (CXADR) fused to tagBFP, generating “humanized” tumors that preserve parental growth characteristics while acquiring high susceptibility to group B Coxsackieviruses (CVBs) and adenovirus serotype 5. Results: CXADR expression in CT-2A, GL261, and B16 cells markedly enhanced binding, internalization, and replication of CVBs in vitro, with the strongest effect observed for LEV14 (attenuated CVB5), which reached up to 10⁵-fold higher viral titers in humanized cells compared with parental cells. Unchanged sensitivity to vesicular stomatitis virus indicated receptor-specific effects. Humanized CT-2A-CXADR-BFP and GL261-CXADR-BFP cells initiated aggressive subcutaneous and intracranial tumors in syngeneic C57BL/6 mice without signs of immune rejection, and histology and MRI confirmed invasive high-grade glioma phenotypes. In intracranial CT-2A-CXADR-BFP tumors, repeated intratumoral LEV14 administration induced extensive tumor necrosis and prolonged survival despite the rapid development of neutralizing antibodies. Systemic intravenous LEV14 dosing produced strong oncolytic activity against subcutaneous CT-2A-CXADR-BFP tumors, as demonstrated by pronounced tumor growth inhibition, long-lasting regression in a subset of animals with gliomas, and improved overall survival. Conclusions: Collectively, these data establish CXADR-humanized models as versatile, immunocompetent platforms for evaluation of CXADR-dependent oncolytic enteroviruses. Full article

Epigenetic dysregulation is increasingly recognized as a key driver of glioblastoma (GBM), with bromodomain-containing protein 4 (BRD4) emerging as a critical regulator of tumor malignancy. GBM is an aggressive brain tumor marked by diffuse infiltration, a population of stem-like cells and multiple resistance mechanisms, which together render it largely incurable. Standard treatment, consisting of surgical resection followed by radiotherapy and temozolomide chemotherapy, confers only limited therapeutic benefit, while a member of the bromodomain and extra-terminal (BET) family, BRD4, regulates transcriptional programs essential for oncogene activation, chromatin stability and glioma cell survival. Its expression is markedly elevated in GBM relative to normal brain tissue, implicating BRD4 in tumor initiation, progression and therapeutic resistance. Recent advances have enabled the development of selective BRD4 inhibitors and degraders capable of penetrating the blood–brain barrier and preferentially targeting glioma cells. Preclinical and early-phase clinical studies indicate that these agents suppress tumor growth and may enhance the efficacy of existing treatments. Although BRD4 clearly influences glioma progression and modulates key oncogenic pathways, the precise mechanisms underlying BRD4-driven gliomagenesis remain only partially understood. Ongoing research continues to advance knowledge of its multifaceted functions. This review summarizes current knowledge on BRD4 in GBM, evaluates emerging BRD4-targeted therapeutic strategies and outlines major challenges and future directions for clinical translation. Full article

In most AFM nanoindentation experiments on soft biological samples, classical contact mechanics models, such as Hertz or Sneddon’s equations, are commonly employed to determine the Young’s modulus. However, biological materials are inherently heterogeneous, and their mechanical properties often depend on the indentation depth. In this work, we present a novel and simple approach to quantify how the apparent modulus varies with increasing indentation depth. The method is based on the general indentation equation for axisymmetric indenters combined with a straightforward polynomial fitting of the force–indentation data. The proposed approach offers significant advantages, as it greatly simplifies the fitting process without requiring any advanced algorithms, while maintaining high accuracy. In addition, it is shown that the depth-dependent mechanical properties of cells can be described by a simple law, $E\left(h\right)=C_d/h+E_l$ , where $E_l$ is the limiting value of the apparent modulus at large indentations, and $C_d/h$ represents the depth-dependent contribution dominant at the initial stages of the indentation process. Here, $C_d$ is a positive stiffness coefficient, and $h$ is the indentation depth. This is a very important result, indicating that by using the pair of coefficients $C_d$ and $E_l$, we can fully describe the mechanical properties of cells, capturing their depth-dependent mechanical behavior. Experiments on fibroblasts and H4 human glioma cells confirm the accuracy of this equation. The proposed methods provide an accessible and reliable framework for nanoscale mechanical characterization, offering insights into the depth-dependent elasticity of heterogeneous soft materials and revealing mechanical patterns in biological samples. Full article

Gliomas are the most prevalent primary malignant neoplasms of the central nervous system, distinguished by their high recurrence rates and poor prognosis. Aerobic glycolysis in tumors generates excess lactate, which promotes lactylation, a post-translational modification (PTM). Although accumulating evidence implicates lactylation in glioma initiation and progression, previous lactylation-focused prognostic studies lacked single-cell resolution and broad validation, limiting their generalizability and clinical relevance. Single-cell and bulk RNA sequencing (RNA-seq) data were integrated to identify lactylation-enriched tumor cell populations and derive candidate genes. A risk model was developed using univariate Cox regression and the Least Absolute Shrinkage and Selection Operator (LASSO), and its predictive performance was validated in independent cohorts from the China Glioma Genome Atlas (CGGA). To improve clinical applicability, a nomogram integrating the risk score incorporating key clinical variables was constructed and externally validated. The risk groups showed distinct immune microenvironment profiles and differential drug sensitivity patterns. In this study, we established and validated a lactylation-related gene signature, with the derived risk score serving as a reliable prognostic biomarker for glioma. Furthermore, the model not only predicts overall survival (OS) but also exhibits the potential to inform drug selection and stratify patients for more precise and personalized therapeutic interventions. Full article

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape. This conversion led to the strong upregulation of neuronal markers (e.g., MAP2 and GAD67) and suppression of glial identity. Functionally, DLC79 treatment inhibited glioma malignancy in vitro, impairing proliferation, migration, invasion, and clonogenicity. In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm. Full article

The brain’s extracellular matrix (ECM) serves as a dynamic and instructive regulator of glioma progression. The ECM provides structural support while integrating pharmacological and mechanical signals that influence glioma initiation, progression, and treatment resistance. Deviant ECM remodeling fosters tumor heterogeneity, invasion, and immune evasion by altering stiffness, composition, and cellular matrix signaling. We proposed that ECM remodeling in gliomas not only facilitates tumor growth and heterogeneity but also establishes advantageous biophysical and metabolic conditions that foster treatment resistance and recurrence. Our objective is to analyze current findings regarding the structural, biochemical, and mechanical roles of the brain ECM in glioma growth, emphasizing its contribution to tumor heterogeneity, mechanotransduction, immunological modulation, and its potential as a therapeutic target. Method: A comprehensive literature review was conducted using scientific databases including PubMed, Web of Science, and Scopus. Peer-reviewed literature published between 2000 and 2025 was selected for its relevance to ECM composition, stiffness, remodeling enzymes, extracellular vesicles, and mechanobiological processes in gliomas. Results: Recent investigations demonstrate that glioma cells actively alter the ECM by secreting collagens, laminins, and metalloproteinases, establishing a feedback loop that facilitates invasion and resistance. Discussion: Mechanical variables, such as ECM stiffness and solid stress, influence glioma growth, metabolism, and immune exclusion. Moreover, extracellular vesicles facilitate significant extracellular matrix remodeling and improve communication between tumors and stromal cells. The disruption of ependymal and subventricular extracellular matrix niches enhances invasion and cerebrospinal fluid-mediated signaling. The remodeling of the ECM influences glioma growth through interconnected biochemical, mechanical, and immunological mechanisms. Examining ECM stiffness, crosslinking enzymes, and vesicle-mediated signaling represents a potential therapeutic approach. Integrative methodologies that combine mechanobiology, imaging, and multiomics analysis could uncover ECM-related vulnerabilities to improve glioma treatment. Full article

Chronic inflammation is a well-established hallmark of cancer, playing a critical role in the initiation and progression of gliomas. Recent evidence underscores the importance of anti-inflammatory natural products as chemotherapeutic and potentially as chemopreventive agents, offering a safe and multifaceted approach to mitigate tumor-promoting inflammation in the brain. This review explores the interplay between major inflammation-related pathways—such as NF-κB, COX-2, and the NLRP3 inflammasome—and key bioactive compounds derived from natural sources such as polyphenols, isothiocyanates, terpenes/lignans, and omega-3-derived mediators. We provide evidence on the effect of these compounds on the above inflammatory triangle. We discuss emerging in vitro, in vivo preclinical and translational evidence in the context of glioma biology and highlight how these compounds may pass the blood–brain barrier (BBB) and modulate the tumor microenvironment (TME), including immune cell infiltration and cytokine profiles that may act in a pro- or anti-inflammatory manner, highlighting their capacity to inhibit GBM-associated inflammation. Each substance may differentially influence the components of the inflammatory triangle. Overall, we position these agents as low-toxicity, formulation-aware adjuncts to standard care. The ultimate goal is offering novel insights on low-toxicity, inflammation-targeting interventions against malignant brain tumors. Full article