Ex Vivo Characterization Studies Identify Candidate Therapies for the Individualized Care of NF2-Related...

Background/Objectives: NF2-related schwannomatosis (NF2-SWN) is a genetic tumor predisposition syndrome of the nervous system caused by pathogenic variants in NF2 encoding the merlin tumor suppressor. Truncating variants in NF2 cause severe phenotypes with higher tumor burden, early mortality, and a lifetime need for multiple surgeries due to lack of medications that control schwannoma growth. Methods: We developed a functional precision medicine (FPM)-inspired workflow to identify drug sensitivities in cells isolated from a pediatric severe NF2-SWN patient's spinal and peripheral schwannomas. Transcriptomic profiling, high-content drug sensitivity assays, tissue and isolated cell immunostaining, flow cytometry, and capillary-based immunoblotting were used to study the available tissues. Results: Aberrant merlin-dependent pathway expression was conserved between the spinal schwannoma and its cultured primary cells. Drug sensitivity screens in 2- and 3-dimensional formats revealed cytotoxic effects of fimepinostat in primary cells; dasatinib with brigatinib was the most effective cytostatic combination. Ineffective therapies attempted in the patient were also ineffective ex vivo. Conclusions: These data support the idea of using the FPM workflow to improve and individualize the standard of care for severe NF2-SWN patients using surgical samples.