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

doi:10.1172/JCI168035

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. FranzJonathan Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English (US)
Article number	e168035
Journal	Journal of Clinical Investigation
Volume	133
Issue number	12
DOIs	https://doi.org/10.1172/JCI168035
State	Published - Jun 15 2023

Funding

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 Biorepository, 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. 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.

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General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI168035

Cite this

Drumm, M. R., Wang, W., Sears, T. K., Bell-Burdett, K., Javier, R., Cotton, K. Y., Webb, B., Byrne, K., Unruh, D., Thirunavu, V., Walshon, J., Steffens, A., McCortney, K., Lukas, R. V., Phillips, J. J., Mohamed, E., Finan, J. D., Santana-Santos, L., Heimberger, A. B., ... Horbinski, C. (2023). Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors. Journal of Clinical Investigation, 133(12), Article e168035. https://doi.org/10.1172/JCI168035

@article{86cf20fa126b43c2b67cd693d2b77426,

title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, Drumm et al.",

year = "2023",

month = jun,

day = "15",

doi = "10.1172/JCI168035",

language = "English (US)",

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Drumm, MR, Wang, W, Sears, TK, Bell-Burdett, K, Javier, R, Cotton, KY, Webb, B, Byrne, K, Unruh, D, Thirunavu, V, Walshon, J, Steffens, A, McCortney, K, Lukas, RV, Phillips, JJ, Mohamed, E, Finan, JD, Santana-Santos, L , Heimberger, AB , Franz, CK, Kurz, J, Templer, JW , Swanson, GT & Horbinski, C 2023, 'Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors', Journal of Clinical Investigation, vol. 133, no. 12, e168035. https://doi.org/10.1172/JCI168035

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

AU - Templer, Jessica W.

AU - Swanson, Geoffrey T.

AU - Horbinski, Craig

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

Abstract

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