High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas

Abstract

Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.

Histone deacetylase inhibitors enhance oncolytic herpes simplex virus therapy for malignant meningioma

“…Both TSA and Pano exhibited high cytotoxicity to human MM cells in vitro at sub-micromolar dose ranges, direct anti-tumor activity consistent with what was shown in breast cancer cell lines [ 40 ]. Pano was previously identified as a potent hit in a screening of an epigenetic compound library tested only at 1 μM final dose in a panel of human meningioma cell models, including IOMM-Lee and CH157 cells [ 41 ]. We chose HDACi concentrations that were minimally cytotoxic on their own, in order to isolate their potential to sensitize MM cells to oHSV treatment.…”

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

“…In this study we present a 43-meningioma tumor cohort screened against a 139-compound epigenetic inhibitor library. This cohort represents a large increase in total tumors from our prior study 22 , allowing us to investigate clinically relevant subgroups. Overall, HDACi was the most effective class of inhibitor in the cohort, with panobinostat showing the greatest efficacy and significantly reducing cell viability in 36 of 43 tumors.…”

“…3b, ►Supplementary Table S6B). Finally, for the single grade 3 tumor, UNC0631 was the most effective compound (22 HDACi, and 5 were G9a inhibitors (►Fig. 2c, ►Supplementary Table S6C).…”

“…All rights reserved. meningiomas broadly 22 . However, we were previously unable to shed light on important clinical analyses such as tumor grade, prior treatment, recurrence status, or patient gender due to an under-powered cohort.…”

ITF2357 Induces Cell Cycle Arrest and Apoptosis in Meningioma Cells

“…The HDAC inhibitors Panobinostat, LAQ824 and HC have been found to reduce the viability of meningioma cells [12]. but the mechanism of action in meningioma has not been elucidated.…”