"One of the more gratifying aspects of this research is this bedside-to-bench aspect of it," Horbinski said. The findings provide a basis for treating seizures in human glioma patients, Horbinski said, adding that he and his team will be following multiple international clinical trials already underway to further confirm the results. But what was especially exciting is that we were able to substantially reduce those seizures by treating the cultures as well as the animals with an inhibitor that's specifically designed to block the IDH mutant enzyme from working." "We were able to show this in cultured neurons as well as in animal models of IDH mutant gliomas. "We've showed definitively that the chemical product of the IDH mutant enzyme, which is called D-2-hydroxyglutarate, is responsible for causing increased neuronal network bursting, and that's basically the experimental equivalent of a seizure," Horbinski said. The inhibitor reduced seizure activity in mice with IDHmut gliomas by more than 50 percent, according to the study. In an effort to inhibit IDHmut, Horbinski and his collaborators introduced AG881, a newly discovered small molecule inhibitor which can cross the blood-brain barrier. Investigators then observed that mice grafted with IDHmut glioma cells experienced seizure activity nearly five times as often as mice with IDHwt gliomas. Horbinski's previous research has shown that gliomas with mutations in the IDH (IDHMut) gene are more likely to cause seizures because the mutated gene produces D-2-hydroxyglutarate (D2HG), a chemical which excites neurons and leads to an increase in seizure activity. So, we explored it further and found out, yes, there was indeed a patient-based connection where IDH mutant gliomas had more seizures, both before and after surgery." You would think they would cause more seizures in patients, but it was just the opposite. "That was a little surprising because IDH wildtype glioblastomas are inherently much more aggressive, more tissue destructive. Lurie Comprehensive Cancer Center of Northwestern University. "When during chart reviews for an unrelated study, I discovered that IDH mutant glioma patients seemed to be having a lot of problems with seizures, more so than IDH wild-type glioblastoma patients did," said Horbinski, who is also director of the Pathology Core Facility at the Robert H. Most adult-type diffuse glioma patients will experience at least one seizure during the course of the disease and they're often difficult to control with medication.Ĭraig M Horbinski, MD, Ph.D., director of Neuropathology in the Department of Pathology and senior author of the paper, said the idea for the study came to him as he was conducting chart reviews for his glioma patients. Adult‐type diffuse gliomas are the most common malignant tumors arising in the central nervous system, affecting six in 100,000 worldwide, according to the National Institutes of Health.
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