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The role of dordaviprone in the multidisciplinary management of diffuse midline glioma

Abdullah M Al Lawati1, Mohammed K Al Suleimani1, Iman A Al Rasbi2

  • 1Department of Surgery, Sultan Qaboos University Hospital, Muscat, Oman.

Surgical Neurology International
|June 3, 2026
PubMed
Abstract

Insights

Dordaviprone (ONC201) shows promise as a targeted therapy for diffuse midline glioma (DMG), effectively crossing the blood-brain barrier. This drug offers a new treatment option with durable activity and manageable side effects for patients with H3K27M-mutant DMG.

Area of Science:

  • Neuro-oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Diffuse midline glioma (DMG) is an aggressive pediatric and young adult brain tumor with limited treatment options.
  • Current treatments like surgery and radiotherapy have limited efficacy due to tumor infiltrative nature and poor blood-brain barrier (BBB) penetration of chemotherapy.
  • Dordaviprone (ONC201) is a novel agent that crosses the BBB and targets H3K27M-mutant DMG.

Purpose of the Study:

  • To evaluate the efficacy and safety of dordaviprone (ONC201) in patients with H3K27M-mutant diffuse midline glioma.
  • To explore the therapeutic potential of a novel agent targeting specific molecular alterations in DMG.

Main Methods:

  • A structured literature search was conducted across major databases (PubMed, Scopus, Google Scholar, ClinicalTrials.gov) from 2015-2025.
  • Emphasis was placed on recent studies and clinical trials involving dordaviprone (ONC201) and H3K27M-mutant DMG.
  • Key search terms included ONC201, dordaviprone, H3K27M, ClpP, DRD2 antagonism, and DMG clinical trials.

Main Results:

  • Dordaviprone (ONC201) demonstrates dual-mechanism action via ClpP activation and DRD2 antagonism, inducing tumor cell death.
  • The drug exhibits selective efficacy in preclinical and clinical studies, crossing the BBB effectively.
  • Dordaviprone is orally administered weekly, is well-tolerated, and presents manageable side effects like fatigue and nausea.

Conclusions:

  • Dordaviprone (ONC201) represents a significant advancement in targeted systemic therapy for diffuse midline glioma.
  • The drug offers proven safety, good tolerability, and meaningful clinical benefit for patients with H3K27M-mutant DMG.
  • Accelerated FDA approval in 2025 highlights the therapeutic potential of dordaviprone for this challenging malignancy.
Keywords:
Diffuse midline gliomaDordaviproneH3K27M mutationONC201Targeted therapy

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