Diffuse midline glioma, a type of rare and often fatal brain cancer, affects 2,000 children and young adults in the United States every year. Thanks to research at the UNC School of Medicine and a collaboration with Madera Therapeutics, a new FDA-approved therapy offers hope to patients and their families.
Dordaviprone (Jazz Therapeutics) is a capsule patients take once a week. Research shows it shrinks the tumor and extends the lifespan of patients. It is the first therapy approved for this specific type of cancer and shows promise in treating other forms of cancer.
Lee Graves, PhD, a professor in the Department of Pharmacology and an expert on anti-cancer therapeutics, and other researchers at the UNC School of Medicine were the first to discover how exactly dordaviprone (also known as ONC201) and related compounds from Madera Therapeutics, interacted with the body to stop cancer in its tracks.
Lee M. Graves, PhD
"These compounds are able to weaken the cancer cells by cutting off its internal power source," said Graves, a member of the UNC Lineberger Comprehensive Cancer Center. "Knowing what we know now, dordaviprone has great potential to transform therapies in cancer, including combinations with standard-of-care treatments, and offer hope for patients with difficult-to-treat cancers."
What Is Diffuse Midline Glioma?
A diagnosis of diffuse midline glioma can be devastating.
The rare and aggressive brain tumor is driven by a specific genetic mutation, termed H3 K27M, in brain cells. The cancer forms in the central structures of the brain, including the brainstem and the spinal cord, resulting in headaches, difficulty with balance, blurred vision, and other neurological symptoms.
Surgery can help shrink the tumor, but its precarious location in the brain makes surgical intervention risky. Researchers and pharmaceutical companies have been trying to come up with a different approach-one that is more targeted and effective.
In 2018, Madera Therapeutics, based in Cary, NC, approached Graves to see how a recently discovered compound, ONC201, and other closely related small molecules performed in models of breast cancer. In the lab, Graves showed that ONC201 stopped cancer cell growth remarkably well.
But there was one problem: researchers didn't know how.
How Dordaviprone Works in Cancer Cells
Graves took on the challenge. Along with Paul R. Graves, PhD at New York-Presbyterian Brooklyn Methodist Hospital, he discovered that ONC201 performs its anti-cancer function by binding to a specific enzyme within the mitochondria of cancer cells.
Tumor shrinkage after 50 weeks of exposure to ONC201. Credit: Chi et al (2019).
Here's how it works:
- An enzyme within the mitochondria, known as caseinolytic protease P (ClpP) is locked in the "on" position by the compound.
- The enzyme then goes into overdrive, eating away at mitochondrial proteins that are responsible for creating energy in cancer cells.
- When the drug switches on ClpP, it throws the cancer cell's energy system into decline.
"Simply put, these compounds are able to weaken the cancer cells by cutting off its internal power source," Graves explained.
FDA Approves the First Therapy for Diffuse Midline Glioma
In May 2019, Graves and team described their findings in a paper in ACS Chemical Biology.
The paper provided crucial data about the compound's anti-cancer properties. The makers of dordaviprone, Jazz Pharmaceuticals, cited the paper when seeking FDA approval of dordaviprone, which used ONC201 as its baseline compound.
On August 6th, 2025, the U.S. Food and Drug Administration granted dordaviprone accelerated approval for adult and pediatric patients age 1 and older with diffuse midline glioma harboring an H3 K27M mutation.
Potential Applications Beyond Brain Cancer
With this achievement in the books, researchers are now determined to see how to optimize and expand use of the drug.
Graves is particularly interested in how the therapy can be used in combination with other standard cancer therapies to boost efficacy. Researchers are also working on expanding its use to treat other cancers, such as breast cancer, head and neck cancer, colorectal cancer, and leukemia.
"Children are living quite a bit longer than expected with this drug," said Graves. "It's got us wondering, can we make it work even better? How can we improve the response for all cancer patients? These are some of the driving questions moving us forward."
The research was made possible by an Innovation Grant from the UNC Lineberger Comprehensive Cancer Center, which provided early support for testing novel cancer therapies.
"I feel very excited that it came from a pilot grant from Lineberger, which is exactly what those grants are supposed to do," said Graves. "These grants are meant to stimulate discoveries and breakthroughs, and it allowed us to do this critical work and make a difference for cancer patients."
Other notable contributors to this research include Nathaniel Moorman, PhD, associate professor in the UNC Department of Microbiology and Immunology, Ekhson Holmuhamedov, PhD, adjunct associate professor in the UNC Department of Pharmacology, and Laura Herring, PhD, associate professor of pharmacology and Director of the UNC Metabolomics and Proteomics Core.
