Activity of PDGFRA inhibitor Avapritinib in H3K27M Diffuse Midline Glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222457 | GEO | 2026/01/01
REPOSITORIES: GEO
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Project description:Mutations in the gene encoding histone H3, p.K28M(K27M) and p.G35R/V(G34R/V), are the major driver gene mutations in gliomas. H3 p.K28M(K27M) mutations are frequently found in gliomas arising in midline structures, so called H3K27M-diffuse midline glioma (DMG), while H3 p.G35R/V(G34R/V) mutations are frequently found in pediatric hemispheric gliomas, so called H3G34R/V-diffuse hemispheric glioma (DHG). In contrast, hemispheric glioma with H3 p.K28M(K27M) mutation, known as H3K27M-DHG, is a rare entity and its clinical and molecular characteristics remain to be fully elucidated. We describe a 41-year-old female patient with the right parietal lobe tumor. Following a gross total resection, the pathology showed a high-grade astrocytoma. Sanger sequencing revealed an H3K27M mutation and an IDH1/2-wildtype, leading to the integrated diagnosis of H3K27M-DHG. She underwent chemoradiotherapy with temozolomide and suffered recurrences twice until her death 55 months after the initial diagnosis. The deoxyribonucleic acid methylation profiling classified the tumor as DMG, H3K27-altered, suggesting that it molecularly belonged to the variant of DMG despite a non-median location. Next-generation sequencing on the recurrent tumor detected fibroblast growth factor receptor (FGFR)1 mutation, a favorable prognostic factor in H3K27M-DMG. A relatively prolonged survival of our patient suggests that FGFR1 mutations may also contribute to a better prognosis in H3K27M-DHG.
2025-12-31 | GSE286743 | GEO
Project description:Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader, SGF29, reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, and metabolism. Finally, we find that SAGA/ATAC inhibition may reduce DMG viability by repressing cholesterol metabolism gene expression and show that combinations of cholesterol- and SAGA/ATAC-targeting drugs synergistically reduce DMG growth. These findings reveal a functional link between SAGA/ATAC-dependent chromatin regulation and both transcriptional and metabolic dysregulation underlying DMG malignancy.
2026-01-27 | GSE317275 | GEO
Project description:Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader, SGF29, reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, and metabolism. Finally, we find that SAGA/ATAC inhibition may reduce DMG viability by repressing cholesterol metabolism gene expression and show that combinations of cholesterol- and SAGA/ATAC-targeting drugs synergistically reduce DMG growth. These findings reveal a functional link between SAGA/ATAC-dependent chromatin regulation and both transcriptional and metabolic dysregulation underlying DMG malignancy.
2026-01-26 | GSE317235 | GEO
Project description:Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader, SGF29, reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, and metabolism. Finally, we find that SAGA/ATAC inhibition may reduce DMG viability by repressing cholesterol metabolism gene expression and show that combinations of cholesterol- and SAGA/ATAC-targeting drugs synergistically reduce DMG growth. These findings reveal a functional link between SAGA/ATAC-dependent chromatin regulation and both transcriptional and metabolic dysregulation underlying DMG malignancy.
2026-02-05 | GSE318286 | GEO
Project description:Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting the enzymatic activity of the complex. Paradoxically, PRC2 histone methyltransferase activity is essential in for oncogenic gene repression in DMG tumour cells though downstream molecular mechanisms that are poorly understood. Here, we discover that this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations containing CBX4. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4-cPRC1 is co-opted to drive repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 landscape characteristic of H3K27M-mutant DMG rewires the distribution of distinct cPRC1 complexes such that CBX4-cPRC1 accumulates at sites of H3K27me3 while other cPRC1 formations are reduced. Despite CBX4-cPRC1 accounting for less than 5% all cPRC1 H3K27M-mutant DMG, it acts as the predominant repressor of (Polycomb target) neural differentiation genes in this setting. Our findings link the altered distribution of H3K27me3 with imbalances of CBX-cPRC1 functions and consequent oncogenic gene repression, revealing new disease mechanisms and potential therapeutic opportunities in this incurable childhood brain tumour.
2025-06-24 | PXD047401 | Pride
Project description:Abstract Background: Diffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterized by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. In this study, we sought to investigate whether irradiation leads to senescence induction and explore the efficacy of senolytics against DMG. Methods: We have characterised the senescent phenotype of five genetically heterogeneous H3K27M-altered human DMG cell lines, combining cellular and/or molecular approaches. The sensitivity of senescent cells to Bcl-xL inhibition has been demonstrated in dose/response curves in vitro and in a PDX model of DMG. Results: Here, we show that ionizing radiation induces senescence and SASP responses in both TP53 mutant and wild-type H3K27M-altered human DMG cell lines. We identify Navitoclax as a potent senolytic agent that selectively targets senescent DMG cells into apoptosis by inhibiting Bcl-xL. Related compounds, such as a proteolysis-targeting chimera (PROTAC)-mediated Bcl-xL degradation and a galacto-conjugated form of Navitoclax also show an effective senolytic activity in senescent cancer cells. Finally, we show that a combination therapy of irradiation and Navitoclax results in reduced tumor burden and increased mouse survival in an orthotopic xenograft DMG model. Conclusion: These results offer a rationale for further clinical development of senolytic therapies as part of multimodal treatment approaches for DMG patients/
2025-07-03 | GSE291046 | GEO
Project description:Activity of PDGFRA inhibitor Avapritinib in H3K27M Diffuse Midline Glioma
| PRJNA922137 | ENA
Project description:Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be a key therapeutic strategy against this highly aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition revealed potent and synergistic cytotoxicity across a range of DMG cultures, with H3K27M-mutant cells demonstrating heightened sensitivity. These results were recapitulated in vivo, significantly extending survival in three independent orthotopic PDX models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility, synergizing with BET inhibition to disrupt transcription, silencing several key oncogenes including MYC, PDGFRA and MDM4, alongside alterations to the splicing landscape. Combined, these data highlight the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, proposing a novel strategy for combating this devastating pediatric brain tumor.
2025-12-22 | GSE272131 | GEO
Project description:Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be a key therapeutic strategy against this highly aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition revealed potent and synergistic cytotoxicity across a range of DMG cultures, with H3K27M-mutant cells demonstrating heightened sensitivity. These results were recapitulated in vivo, significantly extending survival in three independent orthotopic PDX models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility, synergizing with BET inhibition to disrupt transcription, silencing several key oncogenes including MYC, PDGFRA and MDM4, alongside alterations to the splicing landscape. Combined, these data highlight the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, proposing a novel strategy for combating this devastating pediatric brain tumor.
2025-12-22 | GSE272129 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.
2022-02-07 | GSE186802 | GEO