A ‘Major’ Breakthrough in Medicine: The First Drug Shown to Improve Survival Rates for Incurable Brain Tumor – ‘This is a major crack in the armor’

The new drug, named ONC201, almost doubled the survival rate for individuals diagnosed with diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) in comparison to earlier patients.

For the first time, a potential medicinal compound, named ONC201, has shown promising results in treating a specific kind of childhood brain tumor that previously lacked effective treatment methods. This compound extended the survival rate almost twofold in patients diagnosed with diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG), compared to earlier data.

This significant breakthrough is presented by an international collective of scientists led by the University of Michigan Health Rogel Cancer Center along with the Chad Carr Pediatric Brain Tumor Center.

The study, which not only highlights results from two preliminary clinical studies but also delves into why ONC201 was effective against these tumors, has been showcased in Cancer Discovery, a publication by the American Association for Cancer Research.

DMGs and DIPGs, especially those with the H3K27M mutation, are known for their aggressive nature, often resulting in a survival period ranging between 11-15 months. These tumors predominantly affect the young population. Presently, radiation is the only mode of treatment, and even its application poses challenges given the tumor’s critical location in the brain.

Carl Koschmann, M.D., a notable contributor to the study, emphasized the complexity of treating this tumor.

“It’s an incredibly difficult tumor to treat.”

He highlighted that before this discovery, “there have been more than 250 clinical trials that have not been able to improve outcomes. This is a major crack in the armor.”

In two separate trials involving ONC201 and a combined 71 patients with the H3K27M mutation in diffuse midline gliomas, the average survival rate was nearly 22 months for those whose tumors hadn’t returned during the study. Almost one in three participants lived beyond the two-year mark.

Interestingly, ONC201’s journey to these clinical tests was unexpected. Originally intended for targeting dopamine receptors seen in a variety of tumors, scientists discovered its ability to cross the blood-brain barrier, crucial for brain tumor medication.

Early trials on glioblastoma didn’t yield positive outcomes, but some DMG patients with the H3K27M mutation showcased more encouraging results. This led to a phase 1 trial for younger H3K27M-mutated DMG patients.

During the study, Dr. Koschmann and co-researcher, Dr. Sriram Venneti, delved deeper into the tumors’ behaviors. By examining cerebrospinal fluid, they observed that ONC201 was interacting with tumor cell mitochondria, leading to an increase in a metabolite named L-2HG. This unexpected finding revealed that L-2HG counters specific tumor signals, making tumor cells mature more and replicate less. This epigenetic change, induced by the H3K27M mutation, was reversed by ONC201, explained Dr. Venneti of Michigan Medicine.

Venneti explained that ONC201’s effectiveness might be due to its ability to reverse the epigenetic alterations induced by the H3K27M mutation. This insight is groundbreaking in understanding the tumor’s response to ONC201.

There’s a buzz of excitement around ONC201 with more clinical studies in the pipeline, some of which will test it alongside other treatments. While acknowledging that doubling the survival rate might not seem enough given the tumor’s deadly nature, Koschmann remains optimistic about the future, envisioning bigger breakthroughs.

“For now we have this patient population that didn’t have a drug before, and now we see many of the tumors responding. We have a platform to build on and we can also explain why it’s working,” he added.

“We are really excited about this study and envision ONC201 becoming standard of care for these patients in the near future,” Venneti added.

Source: 10.1158/2159-8290.CD-23-0131

Image Credit: Getty