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J Neurol Surg B Skull Base 2023; 84(05): 452-462
DOI: 10.1055/a-1885-1257
Original Article

High-Throughput Screening of Epigenetic Inhibitors in Meningiomas Identifies HDAC, G9a, and Jumonji-Domain Inhibition as Potential Therapies

Philip D. Tatman   *
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
2   Medical Scientist Training Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
3   Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Tadeusz H. Wroblewski   *
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
4   Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Anthony R. Fringuello
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Samuel R. Scherer
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
4   Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
William B. Foreman
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
4   Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Denise M. Damek
4   Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
A. Samy Youssef
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Kevin O. Lillehei
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
Randy L. Jensen
5   Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States
,
Michael W. Graner 
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
,
D. Ryan Ormond
1   Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States
› Author Affiliations Funding Funding for this work was acquired through Meningioma Mommas and the Department of Neurosurgery at the University of Colorado, Anschutz Medical Campus. Tissue was acquired by the neurosurgeons and Department of Neurosurgery Team through the Neurosurgery Neural Tissue Bank at the University of Colorado Anschutz Medical Campus. Cell lines were donated by the University of Utah. The authors would like to thank the patients who selflessly consented to donate their tissue for this work.
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Abstract

Background Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mechanisms is understudied for pharmacotherapeutic development for these tumors. The bio-molecular insights and potential therapeutic development of meningioma epigenetics led us to investigate epigenetic inhibition in meningiomas.

Methods We screened a 43-tumor cohort using a 139-compound epigenetic inhibitor library to assess sensitivity of relevant meningioma subgroups to epigenetic inhibition. The cohort was composed of 5 cell lines and 38 tumors cultured directly from surgery; mean patient age was 56.6 years ± 13.9 standard deviation. Tumor categories: 38 primary tumors, 5 recurrent; 33 from females, 10 from males; 32 = grade 1; 10 = grade 2; 1 = grade 3.

Results Consistent with our previous results, histone deacetylase inhibitors (HDACi) were the most efficacious class. Panobinostat significantly reduced cell viability in 36 of 43 tumors; 41 tumors had significant sensitivity to some HDACi. G9a inhibition and Jumonji-domain inhibition also significantly reduced cell viability across the cohort; tumors that lost sensitivity to panobinostat maintained sensitivity to either G9a or Jumonji-domain inhibition. Sensitivity to G9a and HDAC inhibition increased with tumor grade; tumor responses did not separate by gender. Few differences were found between recurrent and primary tumors, or between those with prior radiation versus those without.

Conclusions Few efforts have investigated the efficacy of targeting epigenetic mechanisms to treat meningiomas, making the clinical utility of epigenetic inhibition largely unknown. Our results suggest that epigenetic inhibition is a targetable area for meningioma pharmacotherapy.

Keywords

meningioma - screening - HDAC - G9a - Jumonji domain

* Co-first Authors.


Institutional Review Board Approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of the University of Colorado Anschutz (COMIRB Protocol #13–3007; approval date: November 14, 2019).


Authors' Contributions

Philip D. Tatman: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—original draft, writing—review and editing, visualization. Tadeusz H. Wroblewski: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—original draft, writing—review and editing, visualization. Anthony R. Fringuello: methodology, data curation, investigation, writing—review and editing. Samuel R. Scherer: methodology, data curation, investigation, writing—review and editing. William B. Foreman: methodology, data curation, investigation, writing—review and editing. Denise M. Damek: conceptualization, formal analysis, resources, writing—review and editing. Kevin O. Lillehei: conceptualization, resources, writing—review and editing, funding acquisition. Randy L. Jensen: conceptualization, resources, writing—review and editing. A. Samy Youssef: conceptualization, resources, writing—review and editing. D. Ryan Ormond: conceptualization, resources, writing—original draft, writing—review and editing, supervision. Michael W. Graner: conceptualization, resources, writing—original draft, writing—review and editing, supervision, project administration, funding acquisition.

All authors have read and agreed to the published version of the manuscript.


Supplementary Material



Publication History

Received: 16 February 2022

Accepted: 20 June 2022

Accepted Manuscript online:
25 June 2022

Article published online:
25 August 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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