Scientists have discovered a new potential drug therapy for a rare, incurable pediatric brain tumor by targeting a genetic mutation found in children with the cancer. By inhibiting the tumor-forming consequences of the mutation using an experimental drug called GSKJ4, they delayed tumor growth and prolonged survival in mice with pediatric brainstem glioma.

Also known as diffuse intrinsic pontine glioma (DIPG), the disease occurs when tumors form in the brainstem, which controls essential body functions such as breathing, heartbeat, and motor and sensory pathways. The tumors are inoperable because of their vital location, and radiation and chemotherapy are largely ineffective. Most patients do not survive more than 1 year after diagnosis.

“No significant advances in the survival of DIPG patients have been made over the last few decades, and new therapeutic approaches are desperately needed,” said first author of the study Rintaro Hashizume, MD, assistant professor in neurological surgery at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Working with senior author C. David James, PhD, professor in neurologic surgery, Hashizume focused on a mutation in the H3F3A gene that was recently discovered in the majority of patients with DIPG. The mutation encodes a type of protein called a histone that helps package DNA inside cells. The unexpected finding suggested the mutation had a role in DIPG development.

The mutation leads to reduced histone methylation, a process that influences gene expression. Hashizume hypothesized that pharmacologically restoring histone methylation could prevent tumor formation. He suggested that GSKJ4, a small molecule inhibitor previously reported to increase methylation for immune disorder treatment, could also work for DIPG.

In the study, published in Nature Medicine (2014; doi:10.1038/nm.3716), mice who received GSKJ4 treatment for 10 days survived significantly longer than those in a control group that did not receive GSKJ4.

“We are so excited by these findings, which for the first time provide evidence for pharmacologic treatment connected to a histone mutation,” Hashizume said. “Furthermore, we’ve identified a compound that may be useful for treating DIPG patients with this mutation.”

Now that the investigators know the inhibitor works against DIPG, they plan to conduct future research to see how long its effects can last with longer treatments. They also want to test the drug in combination with radiation in animal models. The ultimate goal is a clinical trial with human patients.

Fast scientific developments made this work possible, as few resources existed until recently to investigate DIPG.

A few years ago, Nalin Gupta, MD, PhD, a surgeon from the University of California San Francisco, and a collaborator on this study, developed a procedure to safely biopsy patients with DIPG, accessing tumor tissue samples of the disease unmarred by radiation and drug therapy. Hashizume modified two of these samples to establish sustainable cell lines, enabling scientists to examine the disease in this study and others.

“We’re hopeful about what these findings might do for children with this disease,” James said.