Search Results (81)

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: Diffuse midline glioma (DMG), H3 K27M-altered, represents a rare group of gliomas arising in midline structures of the central nervous system. Historically regarded as a pediatric entity, it is now increasingly recognized in adults. Although its relative prevalence among all midline diffuse gliomas and its clinical-radiological characteristics are well defined in children, these tumors remain less characterized in adults, and comparative evaluations with H3 K27 wildtype midline diffuse gliomas are limited. Methods: Consecutive adult patients with histopathologically confirmed diffuse glioma (WHO grade ≥ 2) diagnosed between 2016 and 2025 were retrospectively screened for midline tumor location, with systematic revision of imaging and pathology. For identified midline diffuse gliomas, comprehensive clinical, imaging, and immunohistochemical data were collected, and a detailed morphometric analysis was performed. H3 K27 alteration status was established immunohistochemically, with supplementary immunostaining when necessary. Descriptive and comparative analyses were conducted. Results: A total of 5% of the 541 adult diffuse gliomas were midline, and 23% of IDH wildtype midline gliomas were consistent with DMG, H3 K27-altered (all H3 K27M-mutant). The affected patients were significantly younger, and these tumors predominantly involved the thalamus and mesencephalon. Morphometric analyses revealed trends toward fewer high-grade features in H3 K27-altered tumors, with composite scores demonstrating significant discriminatory ability. The overall survival was not significantly different between groups but showed associations with ring-like enhancement as well as adjuvant and salvage therapies in the overall midline cohort. Conclusions: This study provides population-based prevalence estimates for DMG, H3 K27M-altered, and complements the limited literature with comparative clinical-radiological and morphometric data of potential prognostic relevance. Full article

Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. At present, multi-agent chemotherapy and surgery provide only limited effects and the prognosis for patients with recurrent or metastatic disease remains poor, with 5-year survival rates below 30%. These challenges highlight the need for innovative therapeutic approaches targeting osteosarcoma more effectively. Fenretinide, a synthetic derivative of all-trans retinoic acid, has shown significant antitumor activity in various cancers. In a recent high-throughput drug screening study, fenretinide emerged as the most active molecule against diffuse midline glioma over more than 3500 compounds. Fenretinide also demonstrated cytotoxic activity against osteosarcoma cell lines in vitro and in preclinical models and is endowed with a favorable safety and toxicity profile. However, its poor water solubility and limited bioavailability have hindered its clinical translation. To improve fenretinide bioavailability and enhance tumor exposure, different nanotechnology-based drug delivery systems have been proposed. Here we propose a tertiary complex made of fenretinide, bovine serum albumin, and hydroxypropyl-betacyclodextrin, indicated as BSAF. Methods: BSAF was evaluated for the main physico-chemical parameters such as hydrodynamic size, zeta potential, stability to drug leakage, and the biological effect on the osteosarcoma cell line MG63. Results: BSAF showed hydrodynamic size at the nanoscale, enhanced drug solubilization, high drug loading and size stability to dilution, characteristics that make this complex useful for targeted therapy. When tested on the MG63 osteosarcoma cell line, BSAF demonstrated significantly enhanced cytotoxicity, with half-maximal inhibitory concentration (IC₅₀) values ~50% lower than free fenretinide. The complex was more efficient than free fenretinide in inhibiting cell migration as demonstrated by wound healing assay. Live-cell imaging analyses revealed a cytostatic effect at sub-cytotoxic concentrations. Specifically, treatment with concentrations below the IC₅₀ resulted in significantly prolonged cell doubling time, decreased cell divisions, increased cellular sphericity and thickness, and decreased cell area. These morphological changes are more consistent with cell cycle arrest rather than apoptosis. These findings were corroborated by stable dry mass measurements, an indication of a cytostatic state rather than progressive cell death. In addition, cell motility parameters (e.g., instantaneous velocity, track speed, and displacement) at the single-cell and population level were markedly reduced at sub-IC₅₀ concentrations, further supporting a cytostatic phenotype. Conclusions: Collectively, the new BSAF complex showed promise as a potential therapeutic agent for treating osteosarcoma cancer, due to the favorable physico-chemical characteristics and the cytotoxic/cytostatic effects on MG63 cells. BSAF effects may be therapeutically valuable, particularly in preventing tumor recurrence by suppressing the proliferative and migratory potential of residual drug-resistant clones. Unlike conventional anticancer agents that mainly rely on cell death, fenretinide, when complexed, demonstrates a dual capacity to induce both cytotoxic and cytostatic responses, depending on concentrations, potentially overcoming multiple resistance mechanisms that are generally associated with tumor exposure to drug sub-cytotoxic concentrations. Full article

Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive pediatric brain tumors marked by global loss of the repressive H3 lysine 27 trimethylation (H3K27me3). Functionally analogous to the H3 lysine 27 to methionine (H3K27M) oncohistone, EZHIP inhibits Polycomb repressive complex 2 (PRC2), altering genome-wide H3K27me3 distribution and fate commitment. Unlike H3K27M, EZHIP is epigenetically silenced under physiological conditions yet inducible, suggesting context-dependent oncogenic roles. Its intrinsically disordered structure enables multifunctional interactions and biological versatility. Beyond brain tumors, EZHIP has emerged as an oncogenic driver in osteosarcoma, underscoring broader relevance across cancers. This review integrates current insights into EZHIP—from gene discovery and the mechanism of PRC2 inhibition to its emerging roles in metabolism, DNA repair, 3D chromatin regulation, and development. We outline EZHIP’s clinico-pathological significance in pediatric and adult malignancies, with an emphasis on EZHIP-driven hindbrain tumors. Finally, we discuss therapeutic opportunities, from the direct targeting of intrinsically disordered proteins to the indirect modulation of EZHIP-associated epigenetic and metabolic landscapes, highlighting implications for tumor evolution and precision oncology. Full article

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

High-grade gliomas (HGGs) and diffuse midline gliomas (DMGs) in pediatric patients carry a poor prognosis, necessitating the rapid development of novel therapies. Peptide vaccines represent a safe, repeatable, and rational immunotherapeutic modality aimed at inducing potent, tumor-specific T-cell responses. In this review, we define the scope of current progress by arguing that immunogenicity in children with HGG/DMG hinges on three factors: appropriate antigen class (neoantigen vs. TAA), the use of potent immunoadjuvants, and successful navigation of immune suppression. To address the gap between biological promise and clinical reality, we analyze clinical trials targeting shared tumor-associated antigens (e.g., CMV pp65, Survivin) and specific shared neoantigens (H3.3K27M). Crucially, we highlight pivotal data from the PNOC007 trial, where the magnitude of H3.3K27M-specific T-cell expansion correlated directly with significantly longer overall survival (OS), establishing a causal link between pharmacodynamics and clinical benefit. However, the unique challenges of the immunosuppressive tumor microenvironment and the detrimental effect of necessary corticosteroids remain paramount barriers. Future success relies on multi-modal combination strategies, the development of next-generation personalized neoantigen vaccines, and the application of advanced neuroimaging to accurately assess treatment response. Full article

Pediatric diffuse midline gliomas in the brainstem (bDMGs) are malignant primary brain neoplasms with poor prognosis. Conventional dogma cites that biopsy procedures have risks of devastating injury to the eloquent brainstem and have no direct benefit to affected patients. In recent years, the use of augmented reality (AR) adjuncts has demonstrated potential in providing excellent intraoperative three-dimensional (3D) visualization of intracranial structures. Put together, we hypothesize that the application of AR will be useful as a training tool for brainstem biopsy procedures. Anatomical models of bDMG tumors are created and uploaded to an AR application. The processed data is transferred into designated AR head-mounted devices. Briefly, individual 3D-rendered bDMG images are overlaid with an age-matched, life-sized child mannequin in prone position. A virtual stereotactic brain biopsy needle is deployed by the user into the lesion. At the end of the exercise, each user evaluates their trajectory of choice to assess its accuracy. Overall, the participants reported that the AR platform was useful in reviewing technical nuances for brainstem biopsy in a safe environment. This focused, proof-of-concept study adds to the growing body of literature that AR platforms demonstrate feasibility for neurosurgeons in the understanding of challenging operative neuroanatomy. Full article

Despite a specific histone mutation defining the unique genetic makeup, diffuse midline gliomas are heterogeneous tumors with a wide range of morphologic and molecular spectrum. We investigated the feasibility of using hyperpolarized carbon-13(¹³C) MR metabolic imaging to differentiate distinctive molecular features from two H3K27M-mutant, biopsy-originated diffuse midline glioma xenografts. ¹³C MR metabolic imaging data were acquired on a 3T scanner from 12 rats that had been implanted with SF8628 or SF7761 diffuse midline glioma cells in brainstem, following injection of hyperpolarized [1-¹³C]pyruvate. Despite the two tumors’ similar appearance of T₂-hyperintensity throughout the cerebellum and pons without contrast enhancement, ¹³C metabolic imaging data revealed that SF8627 had significantly higher ratios of lactate to pyruvate, lactate to total carbon, and normalized lactate than SF7761. Elevated lactate levels in SF8628 were associated with large amounts of lactate dehydrogenase (LDH)-A and carbonic anhydrase-IX staining in SF8628 compared to SF7761, which implied that the highly hypoxic condition in SF8628 appeared to contribute to the high level of LDH-A enzyme activity, which, in turn, induced the large conversion from hyperpolarized pyruvate to lactate. Our findings suggest that this advanced metabolic imaging technique may be used for the noninvasive characterization of molecular hypoxia and lactate dehydrogenase-A activity in these pediatric brainstem gliomas. Full article

Diffuse intrinsic pontine glioma (DIPG), or as it is newly redefined, diffuse midline glioma (DMG), remains one of the most horrific diagnoses in pediatric oncology. Aggressive and inaccessible to standard treatments, it is generally considered incurable. Focused ultrasound technology has developed over the last several decades as a noninvasive means to target various types of tumors in both adults and children. Recent advances, particularly in low-intensity focused ultrasound (LIFU), have opened new avenues for enhancing drug delivery and modulating the tumor microenvironment in these challenging tumors. This review provides a comprehensive overview of preclinical and clinical research developments in the use of LIFU for pediatric DMGs. We highlight key findings from animal models demonstrating improved blood–brain barrier (BBB) permeability, increased chemotherapeutic and nanoparticle delivery, and potential immunomodulatory effects of LIFU. Emerging clinical studies, including early-phase safety and feasibility trials, are also discussed, with attention to technical parameters, imaging guidance strategies, and biomarkers of response. The review concludes by addressing the challenges of translating LIFU into routine clinical practice, including device optimization for pediatric anatomy, regulatory hurdles, and the need for standardized treatment protocols. Collectively, these recent advances underscore the promise of LIFU as a minimally invasive, image-guided adjunct to current and future therapies for pediatric DMGs, warranting continued research and collaborative clinical efforts. Full article

Brain tumors are unfortunately the most common types of solid tumors in the pediatric population, superseded only by leukemias, and largely bode a poor prognosis. Despite advances in our ability to diagnose and treat pediatric brain tumors, there remains a large unmet need to develop novel therapies to improve patient outcomes. The recent understanding of the molecular drivers of oncogenesis for many of these tumors has led to the engineering of preclinical small animal models which serve as valuable tools for scientists to study the mechanisms of tumor biology, to understand interactions with the tumor microenvironment, and allow for translatable novel therapeutic discovery. This review focuses on the state-of-the art development of preclinical models of two difficult-to-treat pediatric brain tumors: (1) diffuse midline gliomas, the most lethal form of pediatric brain cancer; (2) medulloblastoma, the most common embryonal tumor of the central nervous system. We will then round off this review with a discussion on the emerging use of multi-omics and AI approaches to complement the testing of novel therapies using these in vivo animal models. Full article

High-grade gliomas are aggressive primary brain tumors and often fatal. They are characterized by rapid growth, treatment resistance, and significant heterogeneity both within and between tumors. A growing body of evidence highlights the mitochondria, dynamic organelles essential for energy production, apoptosis regulation, and metabolic rewiring, as a critical driver in glioma progression and treatment resistance. As a result, these insights have sparked growing interest in mitochondrial-directed therapies. This review highlights the distinct metabolic features and mitochondrial processes of glioma, outlining the rationale for targeting mitochondrial function. We discuss recent advances in mitochondrial-targeted therapies, with a focus on caseinolytic protease P (ClpP) agonism as a breakthrough in the treatment of diffuse midline glioma (DMG). Moreover, we discuss the pathogenic link between mitochondrial metabolism and epigenetic regulation, and the potential therapeutic benefit of disrupting this interaction. Full article

The development of drugs for cancer treatment faces critical challenges due to the heterogeneity in cancers, metastatic nature of the disease, lack of efficacy, toxicity, and drug resistance. This makes it quite important to understand the complexities of cancer as well as the limitations of druggable targets. ONC201 (also known as dordaviprone/TIC10/Modeyso^TM), a first-in-class member of the imipridone family, has been shown to kill cancer cells selectively. Recently, it has received FDA approval as the first and only treatment for recurrent H3K27M-mutant diffuse midline glioma. The unique pharmacophore, favorable therapeutic index, ability to induce TRAIL and the integrated stress response (ISR), activation of natural killer cells, and ability to diffuse across the blood–brain barrier are the unique characteristics of ONC201. ONC201 has shown effectiveness against various cancers, and this has been evident in many preclinical studies. ONC201 as a single agent, although useful, has some limitations, which could be addressed by using combination strategies. ONC201 has shown synergism with other drugs, leading to greater tumor cell death or reduced tumor growth. Next-generation imipridones, viz. ONC206 and ONC212, are more potent analogs of ONC201 and exhibit similar characteristics. In this review, we discuss the therapeutic potential of ONC201 and its analogs using combination strategies across different cancers. Full article

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article