Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors
Michael R. Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna Webb, Kayla Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski
Michael R. Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna Webb, Kayla Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski
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Research Article Neuroscience Oncology

Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors

Abstract

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH–wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma–associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Authors

Michael R. Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna Webb, Kayla Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski

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Figure 6

IDHmut inhibitors reduce seizures in IDHmut glioma–engrafted mice.

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IDHmut inhibitors reduce seizures in IDHmut glioma–engrafted mice. (A) I...
(A) IDHmut or IDHwt mouse glioma was treated with vehicle or 30 or 100 nM AG881 for 2 days in vitro. Cell pellets were collected, and intracellular levels of 2HG were assessed with mass spectrometry and normalized to total protein of each cell pellet. IDHmut glioma, n = 4 biological replicates; IDHwt glioma, n = 2 biological replicates. Bars represent mean ± SEM. **P < 0.01 by unpaired, 2-tailed t test (Bonferroni-adjusted P = 0.02). (B) Schematic of therapeutic study of C57BL/6 mice engrafted with IDHmut glioma and treated daily with 5 mg/kg of AG881 or vehicle. (C) EEGs of mice engrafted with IDHmut glioma and treated with vehicle (n = 8) or 5 mg/kg AG881 (n = 5) were blinded to treatment status and time point, and number of epileptiform spikes per hour was counted at baseline and at day 15. Data points represent each mouse, and lines connect the paired EEGs for a given mouse from different time points. Data were analyzed with paired, 2-tailed t test. (D) Maximal tumor diameter was measured from H&E-stained brains engrafted with IDHmut glioma treated with vehicle (n = 8) or 5 mg/kg AG881 (n = 5). Bars represent mean ± SEM. Data were analyzed with unpaired, 2-tailed t test. (E) Schematic of therapeutic study of C57BL/6 mice engrafted with IDHmut glioma and treated daily with 12.3 mg/kg of AG881 or vehicle. (F) EEGs of mice engrafted with IDHmut glioma and treated with vehicle (n = 3) or 12.3 mg/kg AG881 (n = 7) were blinded to treatment status and time point, and scored for percentage of 10-second epochs that contain epileptiform spikes. Data points represent mean ± SEM. Data were analyzed with 2-way ANOVA. (G) Maximal tumor diameter was measured from H&E-stained brains engrafted with IDHmut glioma treated with vehicle (n = 3) or 12.3 mg/kg AG881 (n = 7). Data were analyzed with unpaired, 2-tailed t test.