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9 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
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.
| Setting | Approach | Guideline |
|---|---|---|
| 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. | not mapped |
| 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. | not mapped |
| Recurrent, trial-eligible | GD2 CAR-T (phase 1, Stanford and others), convection-enhanced delivery, epigenetic and combination trials through consortium networks. | not mapped |
| All stages | Early palliative care, steroid-sparing strategies, and support for the family; tissue donation at autopsy has been central to research progress. | not mapped |