New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma.
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ABSTRACT:
SUBMITTER: Argersinger DP
PROVIDER: S-EPMC8582453 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diffuse Midline Gliomas with Histone 3-Lysine-27-Methionine (H3K27M) mutation constitute the majority of Diffuse Intrinsic Pontine Glioma (DIPG), which is the most aggressive form of pediatric glioma with a dire prognosis. DIPG are lethal tumors found in younger children with a median survival <1 year from diagnosis. Discovery of the characteristic H3K27M mutations offers opportunity and hope for development of targeted therapies for this deadly disease. The H3K27M mutation, likely through epigenetic alterations in specific H3 lysine trimethylation levels and subsequent gene expression, plays a significant role in pathogenesis of DIPG. Animal models accurately depicting molecular characteristics of H3K27M DIPG are important to elucidate underlying pathologic events and for preclinical drug evaluation. Here we review the past and present DIPG models and describe our efforts developing patient derived cell lines and xenografts from pretreated surgical specimens. Pre-treated surgical samples retain the characteristic genomic and phenotypic hallmarks of DIPG and establish orthotopic tumors in the mouse brainstem that recapitulate radiographic and morphological features of the original human DIPG tumor. These models that contain the H3K27M mutation constitute a valuable tool to further study this devastating disease and ultimately may uncover novel therapeutic vulnerabilities.
| S-EPMC6400847 | biostudies-literature
Project description:BackgroundDiffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.MethodsWe performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.ResultsDMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.ConclusionsOur results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.
| S-EPMC11003124 | biostudies-literature
Project description:BackgroundAnaplastic ependymoma and H3K27M-mutant diffuse midline glioma are two common subtypes of brain tumors with poor long-term prognosis. The present study analyzed and compared the differences in cell types between two tumors by single-cell RNA sequencing (scRNA-seq) technology.MethodsScRNA-seq was performed to profile cells from cancer tissue from anaplastic ependymoma patient and H3K27M-mutant diffuse midline glioma patient. Cell clustering, marker gene identification, cell type annotation, copy number variation analysis and function analysis of differentially expressed genes were then performed.ResultsA total of 11,219 cells were obtained from anaplastic ependymoma and H3K27M mutant diffuse midline glioma, and these cells categorized into 12 distinct clusters. Each cell cluster could be characterized with specific cell markers to indicate cellular heterogeneity. Five cell types were annotated in each sample, including astrocyte, oligodendrocytes, microglial cell, neural progenitor cell and immune cell. The cluster types and proportion of cell types were not consistent between the two brain tumors. Functional analyses suggest that these cell clusters are involved in tumor-associated pathways, with slight differences in the cells of origin between the two tumors. In addition, cell communication analysis showed that the NRG3-ERBB4 pair is a key Ligand-receptor pair for anaplastic ependymoma, while in H3K27M-mutant diffuse midline glioma it is the PTN-PTPRZ1 pair that establishes contact with other cells.ConclusionThere was intratumor heterogeneity in anaplastic ependymoma and H3K27M mutant diffuse midline glioma, and that the subtype differences may be due to differences in the origin of the cells.
| S-EPMC10880286 | biostudies-literature
Project description:Diffuse midline glioma with H3K27 M alteration is a primary malignant tumor located along the linear structure of the brain, predominantly manifesting in children and adolescents. The mortality rate is exceptionally high, with a mere 1 % 5-year survival rate for newly diagnosed patients. Beyond conventional surgery, radiotherapy, and chemotherapy, novel approaches are imperative to enhance patient prognosis. This article comprehensively reviews current innovative treatment modalities and provides updates on the latest research advancements in preclinical studies and clinical trials focusing on H3K27M-altered diffuse midline glioma. The goal is to contribute positively to clinical treatment strategies.
| S-EPMC10835306 | biostudies-literature
Project description:The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.
| S-EPMC7866294 | biostudies-literature
Project description:BackgroundDiffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT), but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.MethodsWe performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and in our models, quantified purine synthetic flux using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.ResultsDMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novosynthesis and lower activity of purine salvage due to decreased expression of the purine salvage enzymes. Inhibition of de novo synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells adaptively upregulate purine salvage enzyme expression and pathway activity. Silencing the rate limiting enzyme in purine salvage, hypoxanthine guanine phosphoribosyl transferase (HGPRT) when combined with radiation markedly suppressed DMG-H3K27M tumor growth in vivo.ConclusionsH3K27M expressing cells rely on de novo purine synthesis but adaptively upregulate purine salvage in response to RT. Inhibiting purine salvage may help overcome treatment resistance in DMG-H3K27M tumors.
| S-EPMC10543500 | biostudies-literature
Project description:Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M+ tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M+ diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4+ T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M+ diffuse midline glioma.
| S-EPMC10579055 | biostudies-literature
Project description:IntroductionDiffuse midline glioma with H3 K27M mutation is a new tumor entity from 2016 which is highly aggressive and classified as a WHO Grade IV tumor regardless of histopathologic features. DMG is an aggressive tumor with a poor prognosis, predominating in children and rarely in adults. The clinicopathologic features in adults remain poorly characterized.Case presentationHerein we report a case of a 28-year-old female with diffuse midline glioma with pathology confirmation of histone H3 K27M mutation presenting predominately with left upper and lower limb weakness for 3 weeks followed by an event of loss of consciousness and suspicious mass in MRI Brain/CT Brain. It was confirmed by immunoreactive H3K27M with a score of 4+ in neoplastic cells, which revealed Diffuse midline glioma, H3K27M mutant.Clinical discussionDiffuse midline glioma with histone H3-K27M mutation recently classified CNS tumor with grade IV, including both morphologic and molecular features for diagnosis and associated with poor prognosis.ConclusionWe report a case of adult diffuse midline glioma with H3K27M. The prognosis of diffuse midline glioma is poor and dependents solely on H3K27M irrespective of its grade and characteristics. A comprehensive study of diffuse midline glioma on clinical, radiographic, and demographic features in adult is needed.
| S-EPMC9052283 | biostudies-literature
Project description:Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.
| S-EPMC8018027 | biostudies-literature
Project description:BackgroundDiffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted.MethodsWhole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected.ResultsIncreased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial.ConclusionsH3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
| S-EPMC9825316 | biostudies-literature