Method Profile
Screen a broad oncology library at one dose, then measure concentration responses of patient-specific top hits and compare potency with systemic exposure.
Prioritize drug hypotheses in short-term surgical glioblastoma models while assessing exposure constraints.
Reaggregated IDH-wildtype GBM tumor organoids from viable contrast-enhancing tissue; 11 patients, nine newly diagnosed and two recurrent.
25,000 cells per organoid in 384-well plates; day 2 treatment with 166 drugs at 2.5 μM for 72 hours; top five hits per case tested at 8 concentrations.
Models and library
Fresh surgical GBM cell aggregates; NCI AODX oncology library.
Readout and controls
ATP-based CellTiter-Glo 3D; DMSO, untreated and staurosporine controls; secondary dose-response curves.
Responses are normalized to DMSO, initial hits are ranked, and dose-response curves are fitted. Serum Cmax/IC50 is a surrogate exposure comparison.
Two-stage screen and separate marizomib evaluation.
11 patient models in first stage; 10 with top-hit concentration-response data; seven tested with marizomib. Triplicate wells are not independent tumor repeats.
Vehicle/untreated/positive assay controls; drug-class and patient-model comparisons.
Proteasome and selected HDAC inhibitors showed strong ex vivo activity; marizomib was weak in most tested models despite one highly sensitive case.
A two-stage screen tested 166 approved oncology drugs in organoids from 11 glioblastomas. Selected proteasome and HDAC inhibitors showed strong ex vivo activity, while marizomib was weak in most tested models and systemic exposure remained an imperfect proxy for brain delivery.
