New Publication from Sciomics GmbH: Fimepinostat Promotes Apoptosis and Decreases Cytokine Secretion in NF2-Related Human Schwannoma Cells

Nagel, A.; Hass, E.W.; Hayes, H.; Huelbes, L.; Oliveira, S.; Hardin, H.M.; Marasigan, M.; Nisenbaum, E.; Misztal, C.; Telischi, F.F.; et al. Fimepinostat Promotes Apoptosis and Decreases Cytokine Secretion in NF2-Related Human Schwannoma Cells. Int. J. Mol. Sci. 2026, 27, 2636. https://doi.org/10.3390/ijms27062636

https://www.mdpi.com/1422-0067/27/6/2636

Simple Summary

This study focuses on the action of fimepinostat, a dual histone deacetylase (HDAC)/phosphosphoinositide-3 kinase (PI3K) inhibitor in NF2-related schwannomatosis. Decreased tumor sized in a mouse sciatic nerve allograft model accompanied with mechanistic studies on human model cell lines suggests that HDAC inhibition might be a feasible antitumor therapy in NF2-related schwannomatosis.

Abstract

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression.