Gabapentinoids confer survival benefit in human glioblastoma

doi:10.1038/s41467-025-59614-4

Multicenter Study

. 2025 May 15;16(1):4483.

doi: 10.1038/s41467-025-59614-4.

Gabapentinoids confer survival benefit in human glioblastoma

Joshua D Bernstock^#^{1

2

3}, Mulki Mehari^#⁴, Jakob V E Gerstl^#^{5

6}, David M Meredith⁷, Pablo A Valdes⁸, Philip Heesen⁶, Vardhaan S Ambati⁴, Saritha Krishna⁴, Jason A Chen⁵, Harshit Arora^{5

6}, Benjamin R Johnston^{5

9}, Mikias Negussie⁴, Kristina Grieco⁷, Cesar Nava Gonzales⁴, Abraham Dada⁴, Anna B Lebouille-Veldman^{5

6}, Aymen Kabir⁴, Lennard Spanehl^{5

10}, Jasleen Kaur⁴, Sena Oten⁴, Youssef E Sibih⁴, Rania A Mekary^{6

11}, Andy Daniel⁴, John Frederick de Groot^{4

12}, Saef Izzy¹³, Florian A Gessler¹⁰, Scellig Stone⁹, Omar Arnaout⁵, Yi Lu⁵, Bryan D Choi¹⁴, Matthew D Hall^{15

16}, Minesh P Mehta¹⁶, Yazmin Odia¹⁵, Gregory K Friedman¹⁷, E A Chiocca⁵, Pier Paolo Peruzzi⁵, Timothy R Smith^{5

6}, Shawn L Hervey-Jumper¹⁸

Affiliations

¹ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. jbernstock@bwh.harvard.edu.
² Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. jbernstock@bwh.harvard.edu.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. jbernstock@bwh.harvard.edu.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Computational Neuroscience Outcomes Center (CNOC), Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurosurgery, Rostock University Medical Center, Rostock, Germany.
¹¹ School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA.
¹² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹³ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
¹⁶ Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
¹⁷ Division of Pediatrics, Neuro-Oncology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. shawn.hervey-jumper@ucsf.edu.

^# Contributed equally.

PMID: 40374596
PMCID: PMC12081740
DOI: 10.1038/s41467-025-59614-4

Multicenter Study

Gabapentinoids confer survival benefit in human glioblastoma

Joshua D Bernstock et al. Nat Commun. 2025.

. 2025 May 15;16(1):4483.

doi: 10.1038/s41467-025-59614-4.

Authors

Affiliations

¹ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. jbernstock@bwh.harvard.edu.
² Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. jbernstock@bwh.harvard.edu.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. jbernstock@bwh.harvard.edu.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Computational Neuroscience Outcomes Center (CNOC), Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurosurgery, Rostock University Medical Center, Rostock, Germany.
¹¹ School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA.
¹² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹³ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
¹⁶ Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
¹⁷ Division of Pediatrics, Neuro-Oncology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. shawn.hervey-jumper@ucsf.edu.

^# Contributed equally.

PMID: 40374596
PMCID: PMC12081740
DOI: 10.1038/s41467-025-59614-4

Abstract

Neuronal-glioma interactions are increasingly recognized as critical in the development and progression of central nervous system tumors. Recent research highlights that gliomas can integrate into neural circuits through various mechanisms, including the synaptogenic factor thrombospondin-1 (TSP-1). This new mechanistic understanding of cancer neuroscience allows for novel insights into target discovery. Critically, therapies that modulate neuron-tumor interactions remain agnostic to other oncogenic changes within tumor cells yet may still target fundamental drivers of tumor growth. In line with these findings and controlling for critical confounding variables, we demonstrate a survival benefit associated with gabapentin (an antagonist of TSP-1) following surgical resection of newly diagnosed glioblastoma. This retrospective, multi-institutional cohort study included 1,072 patients, with a discovery cohort of 693 patients and an additional 379 patients from a separate site for external validation. Furthermore, our findings indicate that gabapentin administration is associated with reduced serum TSP-1 levels, suggesting its potential as a future biomarker.

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Conflict of interest statement

Competing interests: The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Joshua D. Bernstock has an equity position in Treovir Inc. and UpFront Diagnostics. Dr. Bernstock is also a cofounder of Centile Bioscience and is on the NeuroX1 and QV Bioelectronics scientific advisory boards. Jason A. Chen is a cofounder and holds equity in Verge Genomics. Dr. Chen is also an advisor and holds equity in Gravity Medical Technology. Florian A. Gessler received honoraria from Signus, BBraun, Aesculap, and AstraZeneca. Gregory K. Friedman is supported by Eli Lilly and Company and Pfizer through contracts to UAB. Dr. Smith reports being a cofounder and equity holder of PheBe Health Inc.

Figures

**Fig. 1. Overall survival of postoperative gabapentin in two independent cohorts.**
Cox proportional hazards model controlling for patient age, sex, race, *MGMT* methylation status, postoperative levetiracetam use, other postoperative AED use, EOR, and preoperative KPS was used in both cohorts. A Cox plot of overall survival following initial surgical resection comparing patients who received gabapentin to those who did not at MGB. At last follow-up, 74/103 (71.8%) patients receiving postoperative gabapentin had died, compared to 512/590 (86.8%) patients who did not receive postoperative gabapentin (HR = 0.65; 95% CI = 0.51–0.84). B Cox plot of overall survival following initial surgical resection comparing patients in the UCSF cohort who received gabapentin to those who did not (HR = 0.65; 95% CI = 0.44–0.97). Source data is provided as a Source Data file.

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References

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[1] Fitzmaurice et al. Global, regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 376–393 (2019). - PMC - PubMed

[2] Fitzmaurice et al. Global, regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 376–393 (2019). - PMC - PubMed

[3] Tirosh, I. & Suvà, M. L. Tackling the many facets of glioblastoma heterogeneity. Cell Stem Cell26, 303–304 (2020). - PubMed

[4] Tirosh, I. & Suvà, M. L. Tackling the many facets of glioblastoma heterogeneity. Cell Stem Cell26, 303–304 (2020). - PubMed

[5] Jung, E. et al. Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma. Nat. Commun.12, 1014 (2021). - PMC - PubMed

[6] Jung, E. et al. Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma. Nat. Commun.12, 1014 (2021). - PMC - PubMed

[7] Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell178, 835–849.e21 (2019). - PMC - PubMed

[8] Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell178, 835–849.e21 (2019). - PMC - PubMed

[9] Bernstock, J. D. et al. Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications. J. Neurosurg.133, 655–663 (2019). - PubMed

[10] Bernstock, J. D. et al. Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications. J. Neurosurg.133, 655–663 (2019). - PubMed

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Gabapentinoids confer survival benefit in human glioblastoma

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Gabapentinoids confer survival benefit in human glioblastoma

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