Clinical studies reveal extended survival in diffuse midline glioma patients receiving ONC201 treatment; research also explains the underlying mechanism of the drug’s success.
For the first time, a potential drug candidate has been identified by researchers that show promise in improving outcomes for patients suffering from a specific type of childhood brain tumor that currently lacks effective treatment options. The compound, named ONC201, was observed to nearly double the survival rates for patients diagnosed with diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) when compared to prior patient outcomes.
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 tumors. The paper is published in Cancer Discovery, a journal of the American Association for Cancer Research.
“It’s an incredibly difficult tumor 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 armor.”
A series of brain scans show a tumor shrinking in response to ONC201. Credit: Michigan Medicine
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 tumors 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 tumors, researchers saw that the drug passes the blood-brain barrier, one of the biggest challenges to designing drugs for brain tumors. 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., Ph.D., were trying to figure out what was happening in these tumor cells
Through the trial, they collected cerebrospinal fluid from patients. They used this fluid to analyze metabolic changes and found ONC201 got into the tumor cells and affected mitochondria. Patients who responded to the drug had an increase in a metabolite called L-2HG produced by tumor cells.
Koschmann called the finding “very much unexpected.” The team found that increased L-2HG reversed tumor-defining epigenetic signals causing tumor cells to differentiate more and divide less. The longer patients were on ONC201, the more tumors exhibited these epigenetic reversals.
“This could explain why this patient population was responding so well to the drug because it had this specific epigenetic abnormality that could be turned off by ONC201. The tumors have an epigenetic change caused by the H3K27M mutation and ONC201 metabolically undoes that change,” said Venneti, associate professor of pathology and pediatrics and scientific research director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine.
Additional clinical trials are currently underway, including testing ONC201 in combination with other therapies. Researchers at U-M’s Chad Carr Pediatric Brain Tumor Center are also continuing to look at ways to overcome resistance to ONC201 by using drug combinations.
Koschmann notes that even a near-doubling of survival is not enough for families of patients with this diagnosis, as the tumor remains very lethal. But he hopes this first step will lead to bigger leaps in the future.
“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 said.
“We are really excited about this study and envision ONC201 becoming the standard of care for these patients in the near future,” Venneti said.

News
Unlocking hidden soil microbes for new antibiotics
Most bacteria cannot be cultured in the lab-and that's been bad news for medicine. Many of our frontline antibiotics originated from microbes, yet as antibiotic resistance spreads and drug pipelines run dry, the soil [...]
By working together, cells can extend their senses beyond their direct environment
The story of the princess and the pea evokes an image of a highly sensitive young royal woman so refined, she can sense a pea under a stack of mattresses. When it comes to [...]
Overworked Brain Cells May Hold the Key to Parkinson’s
Scientists at Gladstone Institutes uncovered a surprising reason why dopamine-producing neurons, crucial for smooth body movements, die in Parkinson’s disease. In mice, when these neurons were kept overactive for weeks, they began to falter, [...]
Old tires find new life: Rubber particles strengthen superhydrophobic coatings against corrosion
Development of highly robust superhydrophobic anti-corrosion coating using recycled tire rubber particles. Superhydrophobic materials offer a strategy for developing marine anti-corrosion materials due to their low solid-liquid contact area and low surface energy. However, [...]
This implant could soon allow you to read minds
Mind reading: Long a science fiction fantasy, today an increasingly concrete scientific goal. Researchers at Stanford University have succeeded in decoding internal language in real time thanks to a brain implant and artificial intelligence. [...]
A New Weapon Against Cancer: Cold Plasma Destroys Hidden Tumor Cells
Cold plasma penetrates deep into tumors and attacks cancer cells. Short-lived molecules were identified as key drivers. Scientists at the Leibniz Institute for Plasma Science and Technology (INP), working with colleagues from Greifswald University Hospital and [...]
This Common Sleep Aid May Also Protect Your Brain From Alzheimer’s
Lemborexant and similar sleep medications show potential for treating tau-related disorders, including Alzheimer’s disease. New research from Washington University School of Medicine in St. Louis shows that a commonly used sleep medication can restore normal sleep patterns and [...]
Sugar-Coated Nanoparticles Boost Cancer Drug Efficacy
A team of researchers at the University of Mississippi has discovered that coating cancer treatment carrying nanoparticles in a sugar-like material increases their treatment efficacy. They reported their findings in Advanced Healthcare Materials. Over a tenth of breast [...]
Nanoparticle-Based Vaccine Shows Promise in Fighting Cancer
In a study published in OncoImmunology, researchers from the German Cancer Research Center and Heidelberg University have created a therapeutic vaccine that mobilizes the immune system to target cancer cells. The researchers demonstrated that virus peptides combined [...]
Quantitative imaging method reveals how cells rapidly sort and transport lipids
Lipids are difficult to detect with light microscopy. Using a new chemical labeling strategy, a Dresden-based team led by André Nadler at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and [...]
Ancient DNA reveals cause of world’s first recorded pandemic
Scientists have confirmed that the Justinian Plague, the world’s first recorded pandemic, was caused by Yersinia pestis, the same bacterium behind the Black Death. Dating back some 1,500 years and long described in historical texts but [...]
“AI Is Not Intelligent at All” – Expert Warns of Worldwide Threat to Human Dignity
Opaque AI systems risk undermining human rights and dignity. Global cooperation is needed to ensure protection. The rise of artificial intelligence (AI) has changed how people interact, but it also poses a global risk to human [...]
Nanomotors: Where Are They Now?
First introduced in 2004, nanomotors have steadily advanced from a scientific curiosity to a practical technology with wide-ranging applications. This article explores the key developments, recent innovations, and major uses of nanomotors today. A [...]
Study Finds 95% of Tested Beers Contain Toxic “Forever Chemicals”
Researchers found PFAS in 95% of tested beers, with the highest levels linked to contaminated local water sources. Per- and polyfluoroalkyl substances (PFAS), better known as forever chemicals, are gaining notoriety for their ability [...]
Long COVID Symptoms Are Closer To A Stroke Or Parkinson’s Disease Than Fatigue
When most people get sick with COVID-19 today, they think of it as a brief illness, similar to a cold. However, for a large number of people, the illness doesn't end there. The World [...]
The world’s first AI Hospital, developed in China is transforming healthcare
Artificial Intelligence and its developments have had a revolutionary impact on society, and healthcare is not an exception. China has made massive strides in AI integrated healthcare, and continues to do so as AI [...]