For the first time, researchers discovered a potential drug candidate that improved outcomes for patients suffering from a type of childhood brain tumour that has no effective treatment.

When compared to previous patients, the compound, called ONC201, nearly doubled survival for patients with diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG).

The findings are reported by an international team of researchers led by the University of Michigan Health Rogel Cancer Center and the Chad Carr Pediatric Brain Tumor Center.

In addition to reporting on the results of two early-stage clinical trials, the paper reveals the underlying mechanisms behind the compound’s success in these tumours. The paper is published in Cancer Discovery, a journal of the American Association for Cancer Research.

Diffuse midline gliomas including DIPG with a mutation called H3K27M are particularly aggressive, with an overall survival rate of 11-15 months.

These tumours are most frequently found in children and young adults. The only available treatment is radiation, and even that is difficult as the tumours are located amid brain regions with critical functions.

“It’s an incredibly difficult tumour to treat,” said senior author Carl Koschmann, M.D., associate professor of pediatric neuro-oncology and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine.

“Prior to this study, there have been more than 250 clinical trials that have not been able to improve outcomes. This is a major crack in the armour.”

In two clinical trials testing ONC201 in a total of 71 patients with H3K27M-mutated diffuse midline gliomas, the median overall survival was nearly 22 months for tumours that had not recurred at the time of enrollment. Almost a third of the patients lived longer than two years.

ONC201 took an unusual path to a clinical trial. Initially designed to target dopamine receptors, which are upregulated in many different tumours, researchers saw that the drug passes the blood-brain barrier, one of the biggest challenges to designing drugs for brain tumours.

Initial trials in glioblastoma were not successful, but a small number of patients with DMG that carried the H3K27M mutation had more promising results.

Without understanding why it worked better in these patients, a phase 1 trial was started in children and young adults with H3K27M-mutated DMG.

Meanwhile, Koschmann and co-author Sriram Venneti, M.D., PhD, were trying to figure out what was happening in these tumour cells. Through the trial, they collected cerebrospinal fluid from patients.

They used this fluid to analyse metabolic changes and found ONC201 got into the tumour cells and affected mitochondria. Patients who responded to the drug had an increase in a metabolite called L-2HG produced by tumour cells.

Koschmann called the finding “very much unexpected.” The team found that increased L-2HG reversed tumour-defining epigenetic signals causing tumour cells to differentiate more and divide less.

The longer patients were on ONC201, the more tumours exhibited these epigenetic reversals.