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

Abstract

BACKGROUND: Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mech-anisms 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 comprised of 5 cell lines and 38 tumors cultured directly from surgery; mean patient age was 56.6 years +/- 13.9SD. Tumor categories: 38 primary tumors, 5 recurrent; 33 from females, 10 from males; 32 = grade 1; 10 = grade 2; one = grade 3. RESULTS: Consistent with our previous results, histone de-acetylase 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 vs 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.