gms | German Medical Science

Objective: The management of aggressive meningiomas remains challenging due to limited treatment options beside surgical removal and radiotherapy. High recurrence rates and lack of effective chemotherapies may be reasons for unfavorable prognosis of these patients. Consequently, there is an urgent need to identify effective therapeutic agents.

Methods: For this purpose, we performed a large-scale drug screening utilizing a drug library consisting of 119 FDA-approved antineoplastic drugs (AOD VI) on the anaplastic meningioma cell line NCH93 using CellTiter-Glo (Promega). Based on the lowest half-maximum inhibitory concentrations (IC50), top 4 drugs were selected. Validation of candidate compounds was performed in Ben-Men-1 (WHO°I), NCH93, and IOMM-Lee (WHO°III) cells using crystal violet assay. Proliferation assay was done by manual counting. Cell cycle and cell death analysis using Annexin V/PI were measured by flow cytometry. A heterotopic xenograft mouse model was established by injecting NCH93 cells in the flank of nude SCID mice. After reaching tumor volume of 200 mm^³, mice were randomized intro treatment groups and drugs were administered intraperitoneally.

Results: Large-scale drug screening resulted in the identification of Carfilzomib, Omacetaxine, Ixabepilone, and Romidepsin as potent drugs. Dose-curve analysis revealed IC50 values in the lower nanomolar range for all compounds and all cell lines (0.2 – 16.2 nM). To further substantiate our findings, cell proliferation was significantly reduced by up to 90% by each candidate drug at 10xIC50 after 48h. Furthermore, cell migration was inhibited up to 60% by all candidate drugs at the respective IC50. However, colony formation was only significantly reduced by Carfilzomib. All candidate drugs induced cell cycle arrest at G0/G1 or G2/M phase and subsequently induced apoptosis. Among them, Ixabepilone and Romidepsin profoundly induced apoptosis by up to 70%. Furthermore, all drugs inhibited tumor growth in vivo, with the most pronounced effect for Ixabepilone, reducing tumor volume by 86% compared to control (p<0.001).

Conclusion: In summary, by utilizing a large-scale drug screening library of FDA-approved drugs we were able to identify Carfilzomib, Omacetaxine, Ixabepilone, and Romidepsin as potent antineoplastic agents of which Ixabepilone showed the most pronounced effect. These promising preclinical results warrant further clinical investigation of Ixabepilone for the treatment of aggressive meningiomas.