Erstellung eines pharmakologischen Atlas von Meningeomen

There are no systemic treatment options for patients with recurrent or refractory meningioma. The objective is to create a pharmacological atlas of all FDA-approved oncology drugs in a large cohort of patient-derived meningioma organoids.

Patient-derived meningioma organoids (TOs) were generated from single cell suspensions from freshly resected meningiomas. TOs were treated with semi-logarithmic concentrations spanning from 10 nmol/l to 30 µmol/l by the automated liquid handler Hamilton MicroLAB STAR®. The drug library AODX from the National Cancer Institute consisted of 179 FDA-approved anticancer drugs. The viability was measured with the RealTimeGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. Categorization into sensitive and resistant drug–response groups was based on the IC50 values and each drug"s peak serum concentration (Cmax).

We created a pharmacological atlas of meningiomas by generating dose-response curves of all 179 current FDA-approved oncology drugs in patient-derived tumor organoids from 32 meningioma patients. The cohort consisted of 28 WHO grade 1, and 4 grade 2 meningiomas, including 4 recurrent tumors. In total, 27% (n=50/179) of the drugs demonstrated a median IC50 value below 30 µmol/l, with specific and significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, mTOR, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine with median values of 10, 27, 170, 326, and 330 nmol/l. Dimension reduction methods of IC50 data revealed somehow linear changes in drug sensitivities between meningiomas rather than drug sensitivity clusters. When considering the Cmax/IC50 ratio as a potential predictive marker of treatment response (>1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), the proteasome inhibitor carfilzomib (34.6), and the anthracycline epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further in/ex vivo evaluation.

We provide the first comprehensive insight into the pharmacological landscape of meningiomas. This data might serve as the foundation for future clinical studies on the systemic treatment of aggressive meningiomas.