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Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma
Published on: November 11, 2021
Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201
Andrew S Chi1, Rohinton S Tarapore2, Matthew D Hall3,4
1NYU Langone Health and School of Medicine, New York, NY, USA.
Background:
H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated.
Methods:
Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence.
Findings:
Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms.
Interpretation:
The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.
Insights
ONC201 shows promise in treating H3 K27M-mutant diffuse midline glioma, a rare childhood cancer. This study demonstrates preliminary clinical proof-of-concept for ONC201 in patients with this aggressive brain tumor.
Area of Science:
- Neuro-oncology
- Pediatric oncology
- Molecular targeted therapy
Background:
- H3 K27M-mutant diffuse midline glioma is a fatal pediatric and young adult malignancy with no effective treatments.
- ONC201, a selective dopamine receptor D2/3 antagonist, has demonstrated an excellent safety profile.
- An expanded access program was initiated following a durable response in a patient with H3 K27M-mutant diffuse midline glioma.
Purpose of the Study:
- To evaluate the safety and efficacy of ONC201 in patients with H3 K27M-mutant gliomas.
- To establish a preliminary clinical proof-of-concept for ONC201 in this patient population.
Main Methods:
- An open-label, expanded access study was conducted for patients with H3 K27M-mutant gliomas who had received prior radiation.
- Patients received oral ONC201 weekly; safety, radiographic assessments, and overall survival were monitored.
- Eighteen patients, including adults and pediatric cases of diffuse midline glioma or DIPG, were enrolled.
Main Results:
- Among 14 recurrent disease patients, median progression-free survival was 14 weeks and median overall survival was 17 weeks.
- Three adult patients with recurrent disease remain progression-free for over 40 weeks.
- Two pediatric DIPG patients treated adjuvantly remain progression-free for over 53 and 81 weeks, with reported radiographic regressions and symptom improvements.
Conclusions:
- ONC201 demonstrates preliminary clinical proof-of-concept for treating H3 K27M-mutant diffuse midline glioma.
- The agent shows potential regardless of patient age or tumor location, supporting further clinical investigation.
- These findings provide a rationale for robust clinical testing of ONC201 in this challenging malignancy.
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