TY - JOUR
T1 - Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors
AU - Drumm, Michael R.
AU - Wang, Wenxia
AU - Sears, Thomas K.
AU - Bell-Burdett, Kirsten
AU - Javier, Rodrigo
AU - Cotton, Kristen Y.
AU - Webb, Brynna
AU - Byrne, Kayla
AU - Unruh, Dusten
AU - Thirunavu, Vineeth
AU - Walshon, Jordain
AU - Steffens, Alicia
AU - McCortney, Kathleen
AU - Lukas, Rimas V.
AU - Phillips, Joanna J.
AU - Mohamed, Esraa
AU - Finan, John D.
AU - Santana-Santos, Lucas
AU - Heimberger, Amy B.
AU - Franz, Colin K.
AU - Kurz, Jonathan Elledge
AU - Templer, Jessica W.
AU - Swanson, Geoffrey T.
AU - Horbinski, Craig
N1 - Funding Information:
MRD was supported by NIH grant F30CA243288. DU was supported by NIH grant F32CA216996. EM was supported by NIH grant T32CA151022. CKF was supported by the Belle Carnell Regenerative Neurorehabilitation Fund and NIH grant R01NS113935. GTS was supported by NIH grant R01NS118039. CH was supported by NIH grants R01NS102669, R01NS117104, and R01NS118039, Northwestern University SPORE in Brain Cancer P50CA221747, and the Lou and Jean Malnati Brain Tumor Institute. Histology and microscopy services were provided by the Mouse Histology and Phenotyping Laboratory supported by National Cancer Institute P30CA060553 awarded to Robert H. Lurie Comprehensive Cancer Center. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Additional tissue resources were provided by the UCSF Brain Tumor SPORE Biore-pository, supported by NIH P50CA097257. The authors thank Alyssa Weston for her assistance with the glioma-spheroid studies. AG881 and AGI5198 compounds were provided by Agios (now under Servier) in a research collaboration agreement. Neither Agios nor Servier had any input into the conduct of the research or the results reported.
Publisher Copyright:
© 2023, Drumm et al.
PY - 2023/6/15
Y1 - 2023/6/15
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI168035
DO - 10.1172/JCI168035
M3 - Article
C2 - 37104042
AN - SCOPUS:85163905273
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
M1 - e168035
ER -