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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.
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. More than 200 chemotherapy and targeted agents were tested from 1990 onward and none added benefit over radiotherapy alone, which is why biopsy and molecular diagnosis became standard. 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.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
Gliomas infiltrate along white matter and can cross the corpus callosum, medulloblastoma sits in the cerebellum, and CNS lymphoma favours deep periventricular tissue; none spread through lymph nodes.
No conventional lymphatics: gliomas spread along white matter tracts and, rarely, through cerebrospinal fluid; medulloblastoma can seed the spine.
Same organ: Lactotroph pituitary neuroendocrine tumour (prolactinoma), Somatotroph pituitary neuroendocrine tumour (acromegaly), Corticotroph pituitary neuroendocrine tumour (Cushing disease and silent corticotroph tumour), Gonadotroph pituitary neuroendocrine tumour (non-functioning adenoma), Thyrotroph pituitary neuroendocrine tumour (TSH-secreting), Pineocytoma and pineal parenchymal tumour of intermediate differentiation, Pineoblastoma, Papillary tumour of the pineal region, Choroid plexus carcinoma, Glioma & glioblastoma, Primary CNS lymphoma, Medulloblastoma, Paediatric low-grade glioma, Atypical teratoid/rhabdoid tumour (ATRT), Ependymoma, Craniopharyngioma, Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma, Brain and spinal cord tumours (all types), Astrocytoma, IDH-mutant (grades 2 to 4), Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, Paediatric high-grade glioma (excluding diffuse midline glioma), Meningioma, Brain metastases (secondary brain tumours), Vestibular schwannoma (acoustic neuroma), Central nervous system germ cell tumours (germinoma and non-germinomatous), Spinal cord tumours (intramedullary and intradural), WNT-activated medulloblastoma, SHH-activated medulloblastoma, Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
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.
Dordaviprone (ONC201), FDA accelerated approval August 2025 for patients aged one year and older with progressive disease; re-irradiation is an alternative or addition.
GD2 CAR-T (phase 1, Stanford and others), convection-enhanced delivery, epigenetic and combination trials through consortium networks.
Early palliative care, steroid-sparing strategies, and support for the family; tissue donation at autopsy has been central to research progress.
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Query for this cancer: (TITLE:"Diffuse midline glioma, H3 K27-altered" OR ABSTRACT:"Diffuse midline glioma, H3 K27-altered" OR TITLE:"including DIPG" OR ABSTRACT:"including DIPG" OR TITLE:"DIPG" OR ABSTRACT:"DIPG" OR TITLE:"Diffuse intrinsic pontine glioma" OR ABSTRACT:"Diffuse intrinsic pontine glioma" OR TITLE:"DMG" OR ABSTRACT:"DMG" OR TITLE:"H3 K27M glioma" OR ABSTRACT:"H3 K27M glioma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Diffuse midline glioma, H3 K27-altered (including DIPG), not a curated reading list.
Radiation-only remains standard as more than 200 agents fail to add benefit.
Schwartzentruber and Wu (Nature Genetics) find recurrent histone H3 mutations in DIPG and paediatric glioblastoma.
First histone-defined tumour entity.
Mount and Monje (Nature Medicine) show GD2 CAR-T clears tumours in mouse models.
Majzner and colleagues (Nature) report clinical and radiographic improvement with intravenous then intracerebroventricular dosing.
Durable objective responses in recurrent H3 K27M DMG reported in JCO; ACTION phase 3 open.
FDA accelerated approval on 6 August 2025 for progressive H3 K27M-mutant diffuse midline glioma, the first systemic therapy for the disease.
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