Medikamenten-Kombinationsscreening identifiziert Carfilzomib und Enzalutemid für die Behandlung von aggressiven Meningeomen.

The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or overcoming resistance to single drugs. In search of effective synergistic drug combinations for the treatment of meningiomas, we performed an automated combinatorial drug screening in meningioma cell lines and patient-derived tumor organoids.

Three grade 3 meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response (0-1000 nmol/l) matrices for 48 h by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. To demultiplex cell viability from a single well, the fluorescence signal was used as a surrogate marker for viability. Patient-derived tumor organoids (TOs) were established from single cell suspensions of freshly resected meningioma tissue (total n=20; grade 2 n=1; n=3 recurrent tumors). The cell viability was measured by CellTiterGlo3D. Drug synergism was calculated by the ZIP synergy finder model.

This drug screening effort generated 13,695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in IOMM-Lee (n=157, 1.14%), followed by KT21-MG1 (n=122, 0.88%), and NCH93 (n=75, 0.54%). Next, we validated the 110 most effective drug combinations in wild-type meningioma cells. 75 drug combinations demonstrated a positive most synergistic area (MSA) score, indicating synergistic effects. Next, we selected the 16 most promising combinations based on synergy scores and literature evidence for screening in TOs. The drug combination of proteasome inhibitor carfilzomib and the androgen receptor inhibitor enzalutamide exhibited the highest MSA scores in TOs. In 40% (n=8/20) of the cases, the combination showed strong synergism (MSA>10) resulting in an overall average MSA of 7.36. This was followed by carfilzomib and neratinib, and romidepsin and gemcitabine with average MSAs of 5.49, and 4.32, respectively. Furthermore, carfilzomib and enzalutamide induced apoptosis in TOs assessed by Caspase-3/7 (p<0.01).

This comprehensive combinatorial drug screening identified the synergistic combination of the proteasome inhibitor carfilzomib and androgen receptor inhibitor enzalutamide that can be an effective treatment option for selected meningioma patients.