LAUSR

The mainstay of treatment for progressive or recurrent meningiomas is surgery and/or radiotherapy. Patients with refractory cancer might benefit from systemic treatment options. However, to date, no effective chemotherapy is available for these patients. For this reason, novel inhibitors for the treatment of aggressive meningiomas are urgently needed. Therefore, we used our previously published Affymetrix microarray dataset (GSE74385) consisting of 62 meningiomas enriched with 28 WHO°III MGMs to screen substantially expressed genes that can be targeted by available inhibitors. For each targeted gene, three compounds were selected based on their clinical development. This filter process resulted in 107 drugs targeting 57 different genes. Most compounds were oncology-related (n = 94, 88%) with the remaining compounds being non-oncology agents (n = 13, 12%). Thereafter, a 2-stage screening strategy was employed. First, drugs were screened at a single dose (2.5 µM) in two malignant meningioma cell lines (NCH93 and IOMM-Lee) with CellTiter-Glo (Promega). Only drugs resulting in a cell viability of 50% or less of either cell line were considered for further validation. Remaining drug candidates (n = 33) exclusively belonged to the oncology-related group, consisting of 4 FDA-approved antineoplastic drugs (12%). The other drugs are currently tested in clinical trials (24% in phase III, 39% in phase II, and 24% in phase I). Drug candidates were further analyzed in a six-point dose-response scheme ranging from 0.1 nM to 10 µM in three meningioma cell lines (Ben-Men-1, NCH93, IOMM-Lee). The top 5 drugs were selected based on the lowest mean of z-transformed area under the curve. Resulting drugs and corresponding targets are: OTSSP167 (MELK), Panobinostat (HDAC), Picropodophyllin (IGF-1R), KPT-9274 (PAK4 and NAMPT), and BI-2536 (PLK1). Taken together, our drug screening approach utilized in silico data to identify potential inhibitors for the treatment of aggressive meningiomas warranting further preclinical investigation.