Scientists Discover How to Halt a Fatal Pediatric Brain Tumor

This article was originally published in the Northwestern University Feinberg School of Medicine News Center. 

Every year, about 300 children under the age of 10 years old in the U.S. develop an aggressive pediatric brain tumor, referred to as diffuse intrinsic pontine glioma (DIPG). No children suffering from DIPG have survived longer than one year Northwestern Medicine scientists believe a newfound molecule may be able to buck that trend by stopping the growth of this fatal brain tumor.

“This tumor kills every single kid who gets DIPG within one year. No one survives,” said Andrea Piunti, PhD, the study’s first author and a postdoctoral fellow in the lab of Ali Shilatifard, PhD, chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics.

“To the best of our knowledge, this is the most effective molecule so far in treating this tumor,” added senior author Shilatifard. “Every other therapy that has been tried so far has failed.”

Radiation therapy only prolongs patients’ survival by a few months, he noted.

Previous Research Paves the Way to Testing

Shilatifard’s lab previously identified the pathway through which a mutation causes this cancer in fruit flies. He and colleagues believed the pathway would be a good target to thwart the tumor and pushed forward with their molecular studies. Shilatifard and Piunti collaborated with C. David James, PhD, professor of Neurological Surgery, Rintaro Hashizume, MD, PhD, assistant professor of Neurological Surgery, Craig Horbinski, MD, PhD, associate professor of Pathology and of Neurological Surgery, Rishi Lulla, MD, assistant professor of Pediatrics in the Division of Hematology, Oncology and Stem Cell Transplantation and Amanda Saratsis, MD, assistant professor of Neurological Surgery. Lulla, a pediatric neuro-oncologist, and Saratis, a pediatric neurosurgeon, respectively, are also at the Ann & Robert H. Lurie Children’s Hospital of Chicago. The scientists are also members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In a study with Hashizume’s group, they demonstrated that mice that had the drug delivered through their abdomen had an increased survival of 20 days, which is a long time in the life of a mouse, Piunti said. Now the team at Northwestern Medicine and Lurie Children’s is working on delivering the drug to the brain stem to see if the effect will be more potent.

To test the molecule, scientists took tumor cell lines from a pediatric patient who was untreated and injected those cells into the brain stem of a mouse. The human tumor engrafted in the brain of the mouse. The mouse was then treated with the molecule while scientists monitored the tumor. The molecule stopped the growth of the tumor cells and forced them to turn into other types of cells, known as differentiation, thereby halting its growth.

This molecule detaches proteins, known as bromodomain proteins, from their binding to a mutant protein, the histone H3K27M, which is present in more than 80 percent of these tumors.

While the molecule itself is not yet available commercially, another similar class of molecules, BET inhibitors, is being tested in clinical trials for pediatric leukemia and other types of tumors. These could be used in a clinical trial for the pediatric tumor.

Shilatifard credits the collaborative environment at Northwestern Medicine for making the discovery possible.

“This work could not have been done anywhere in the world except Northwestern Medicine, because of all the scientists and physicians who have been recruited here during the past five years and how they work together to link basic scientific research to the clinic,” Shilatifard said. “This discovery is the perfect example of how we take basic science discoveries and translate them to cure diseases at Northwestern Medicine.”