# Diffuse midline glioma, H3 K27-altered (including DIPG)

Source: https://onco.cc/cancers/dipg-dmg/  
OnCo record `dipg-dmg` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Diffuse midline glioma grows through the brainstem and cannot be removed surgically. A single change in a histone protein (H3 K27M) rewires how the tumour reads its DNA. Radiotherapy was long the only help; in 2025 the first drug aimed at this tumour, dordaviprone (ONC201), was approved after durable shrinkage in some patients, and GD2 CAR-T cells have produced striking early responses.

## Summary

Diffuse midline glioma (DMG), H3 K27-altered, is the WHO 2021 name for the tumour long called diffuse intrinsic pontine glioma when it arises in the pons; it also occurs in the thalamus and spinal cord. Most carry a lysine-to-methionine substitution at position 27 of histone H3 (H3.3 K27M or H3.1 K27M), or an equivalent EZHIP overexpression, which inhibits the PRC2 complex, causes global loss of H3K27 trimethylation and locks cells in a stem-like state. Co-alterations in TP53, ACVR1 (H3.1 tumours), PDGFRA and PIK3CA define subgroups. The tumour infiltrates rather than displaces, so it cannot be resected; stereotactic biopsy is now standard because the molecular diagnosis guides trials and prognosis.

Focal radiotherapy remains the only treatment with a proven effect, temporarily restoring function; re-irradiation at progression is now supported by prospective data. Decades of chemotherapy and targeted-agent trials added nothing. The first change came from an unexpected direction: dordaviprone (ONC201), an imipridone that antagonises the dopamine receptor D2 and activates the mitochondrial protease ClpP, produced durable objective responses in a minority of recurrent H3 K27M tumours in pooled phase 2 data (JCO 2024) and received FDA accelerated approval on 6 August 2025 for progressive H3 K27M-mutant DMG in patients aged one year and older, the first systemic therapy approved for this disease. The phase 3 ACTION trial (NCT05580562) tests it after radiotherapy in newly diagnosed patients. In parallel, GD2-directed CAR-T cells delivered intravenously and into the ventricles (Stanford; Nature 2022 and 2024) have produced radiographic and clinical improvement, including a sustained complete response, alongside a manageable but serious inflammatory swelling syndrome. Convection-enhanced delivery, focused-ultrasound opening of the blood-brain barrier, and combination epigenetic strategies (PRC2 and HDAC axis) are in early trials.

Open problems are the ones that define brain-tumour drug development: getting drugs across the blood-brain barrier into an infiltrating tumour, measuring response in a region where swelling is dangerous, and building trials fast enough for a disease that progresses within months. Groups such as the Pacific Pediatric Neuro-Oncology Consortium, CONNECT and SIOPE HGG, with tissue donation programmes, have turned DIPG from the least studied to one of the best characterised childhood cancers.

## Fields

- Kind: Cancer
- Last checked: 2026-09-10
- Also known as: DIPG; Diffuse intrinsic pontine glioma; DMG; H3 K27M glioma; Paediatric high-grade glioma
- Tags: nci-coverage; paediatric; cns
- Group: paediatric
- Burden: A few hundred children a year in the United States, mostly aged 5 to 10; the leading cause of brain-tumour death in children (NCI PDQ).
- Subtypes: H3.3 K27M (most common; pons, thalamus, spine); H3.1 K27M (younger children, ACVR1 mutations, longer natural history); H3-wild-type with EZHIP overexpression; EGFR-mutant diffuse midline glioma (bithalamic); Adult H3 K27M diffuse midline glioma (thalamic and spinal)
- Biomarkers: H3 K27M by immunohistochemistry or sequencing; Loss of H3K27me3; TP53, ACVR1, PDGFRA, PIK3CA co-alterations; EGFR alteration (bithalamic subtype); Cerebrospinal-fluid cell-free tumour DNA for H3 K27M (in development for monitoring); MRI with diffusion and perfusion for response assessment

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/dipg-dmg/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/dipg-dmg/#overview [4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/dipg-dmg/#what-it-is [5 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/dipg-dmg/#finding-it [6 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/dipg-dmg/#treating-it [4 settings, 2 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/dipg-dmg/#evidence [9 trials, 1 key paper, 7 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/dipg-dmg/#science [6 targets, 2 pathways]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/dipg-dmg/where-you-are/ [4 centres]
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/dipg-dmg/#living-with-it [16 questions]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/dipg-dmg/coming/ [2 medicines, 8 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/dipg-dmg/data/ [47 connected records]

## Standard of care

- Newly diagnosed: Stereotactic biopsy for molecular diagnosis and trial eligibility, then focal radiotherapy (about six weeks; hypofractionated schedules are non-inferior); steroids for symptoms. Enrolment in a trial such as ACTION (dordaviprone after radiotherapy) is recommended. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [ACTION](https://onco.cc/trials/action-dmg/), [Dordaviprone](https://onco.cc/drugs/dordaviprone/))
- Progressive after radiotherapy, H3 K27M-mutant: Dordaviprone (ONC201), FDA accelerated approval August 2025 for patients aged one year and older with progressive disease; re-irradiation is an alternative or addition. ([Dordaviprone](https://onco.cc/drugs/dordaviprone/))
- Recurrent, trial-eligible: GD2 CAR-T (phase 1, Stanford and others), convection-enhanced delivery, epigenetic and combination trials through consortium networks. ([CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)](https://onco.cc/technologies/glioma-car-t/), [GD2 (disialoganglioside)](https://onco.cc/targets/gd2/), [Focused-ultrasound blood-brain barrier opening](https://onco.cc/technologies/bbb-focused-ultrasound/))
- All stages: Early palliative care, steroid-sparing strategies, and support for the family; tissue donation at autopsy has been central to research progress. ([Early integrated palliative care](https://onco.cc/technologies/palliative-care/))

## State of the art

- H3 K27M defines the disease molecularly; biopsy is safe and standard, and cerebrospinal-fluid tumour DNA is emerging as a way to track it.
- Dordaviprone (ONC201) is the first drug approved for DMG (FDA accelerated approval 2025), a mitochondrial-stress and DRD2 mechanism found by screening rather than design; ACTION tests it in newly diagnosed disease.
- GD2 CAR-T cells given into the blood and the ventricles have produced meaningful neurological improvement and at least one durable complete response in early trials, showing the tumour is immunologically reachable.
- Radiotherapy remains the backbone; re-irradiation extends benefit at progression.

## Open problems

- Most tumours still progress; dordaviprone helps a minority and the phase 3 ACTION trial will show whether earlier use extends survival.
- Drug delivery across the blood-brain barrier into infiltrating tumour: convection-enhanced delivery, focused ultrasound and intraventricular cell therapy are being tested.
- Response assessment: swelling and pseudo-progression confound MRI in the brainstem; cerebrospinal-fluid tumour DNA is being validated as a marker.
- Trial speed: a disease measured in months needs platform trials and regulatory paths built for rarity, which the RACE for Children Act and paediatric consortia are meant to provide.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Diffuse_intrinsic_pontine_glioma
- NCI PDQ: childhood astrocytomas and other gliomas (includes diffuse midline glioma): https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq
- FDA: dordaviprone accelerated approval (6 August 2025): https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma
- ACTION phase 3 (NCT05580562): https://clinicaltrials.gov/study/NCT05580562
- GD2 CAR-T in H3 K27M diffuse midline glioma (Nature 2022): https://doi.org/10.1038/s41586-022-04489-4

## Connected records

- cancers: [Astrocytoma, IDH-mutant (grades 2 to 4)](https://onco.cc/cancers/idh-mutant-astrocytoma/), [Brain and spinal cord tumours (all types)](https://onco.cc/cancers/brain-tumours/), [Childhood cancers (all types)](https://onco.cc/cancers/childhood-cancers/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Oligodendroglioma, IDH-mutant and 1p/19q-codeleted](https://onco.cc/cancers/oligodendroglioma/), [Paediatric high-grade glioma (excluding diffuse midline glioma)](https://onco.cc/cancers/paediatric-high-grade-glioma/), [Paediatric low-grade glioma](https://onco.cc/cancers/paediatric-low-grade-glioma/), [Spinal cord tumours (intramedullary and intradural)](https://onco.cc/cancers/spinal-cord-tumours/)
- terms: [Blood-brain barrier (BBB)](https://onco.cc/terms/blood-brain-barrier/), [H3 K27M (diffuse midline glioma)](https://onco.cc/terms/h3k27m/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [RACE for Children Act](https://onco.cc/terms/race-for-children-act/)
- institutions: [ACCELERATE](https://onco.cc/institutions/accelerate-platform/), [German Cancer Research Center (DKFZ)](https://onco.cc/institutions/dkfz/), [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/), [Stanford Health Care / Stanford Cancer Institute](https://onco.cc/institutions/stanford/)
- technologies: [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)](https://onco.cc/technologies/glioma-car-t/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Early integrated palliative care](https://onco.cc/technologies/palliative-care/), [Focused-ultrasound blood-brain barrier opening](https://onco.cc/technologies/bbb-focused-ultrasound/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- targets: [EZH2](https://onco.cc/targets/ezh2/), [GD2 (disialoganglioside)](https://onco.cc/targets/gd2/), [H3-3B](https://onco.cc/targets/h3-3b/), [H3C14](https://onco.cc/targets/h3c14/), [H3C2](https://onco.cc/targets/h3c2/), [Histone H3.3 (H3-3A)](https://onco.cc/targets/h3-3a/)
- drugs: [Dordaviprone](https://onco.cc/drugs/dordaviprone/), [Temozolomide](https://onco.cc/drugs/temozolomide/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/), [Guangzhou Virotech Pharmaceutical](https://onco.cc/companies/guangzhou-virotech/), [Innovative Therapies for Children with Cancer (ITCC)](https://onco.cc/companies/itcc/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/)
- trials: [A Study of Cobolimab Plus Dostarlimab in Pediatric and Young Adult Participants With Cancer](https://onco.cc/trials/nct06521567/), [A Study of VRT106 in Combination With Radiotherapy in Adult Patients With Diffuse Midline Glioma / Diffuse Intrinsic Pontine Glioma](https://onco.cc/trials/nct07589257/), [ACTION](https://onco.cc/trials/action-dmg/), [Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG)](https://onco.cc/trials/nct05630209/), [Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric DIPG](https://onco.cc/trials/nct05615623/), [Illuminate: A Clinical Study Evaluating CAR T Immune Cell Therapy (BCB-276) for Patients With Diffuse Intrinsic Pontine Glioma (DIPG).](https://onco.cc/trials/nct07680439/), [NCI-COG Pediatric MATCH (APEC1621)](https://onco.cc/trials/pediatric-match/), [Study of Olutasidenib and Temozolomide in HGG](https://onco.cc/trials/nct06161974/), [Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors](https://onco.cc/trials/nct03709680/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The brain: barrier and sanctuary](https://onco.cc/bottlenecks/b-brain-delivery/)
- key papers: [GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas](https://onco.cc/key-papers/paper-majzner-nature/)
- biomarkers: [H3 K27M mutation](https://onco.cc/biomarkers/h3-k27m/)
- roadmaps: [Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first](https://onco.cc/roadmaps/paediatric-oncology-roadmap/)
- journals: [Brain tumor pathology](https://onco.cc/journals/brain-tumor-pathology/), [CNS oncology](https://onco.cc/journals/cns-oncology/), [Journal of neuro-oncology](https://onco.cc/journals/journal-of-neuro-oncology/)

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JSON: https://onco.cc/api/v1/entities/dipg-dmg.json