Feasibility study of using high-throughput drug sensitivity testing

Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clinical trials investigate treatment effects at population level. Genomics-driven oncology for stratified treatments allow clinical decision making in only a small minority of screened patients. Addressing tumor heterogeneity, we aimed to establish a clinical translational protocol in recurrent GBM (recGBM) utilizing autologous glioblastoma stem cell (GSC) cultures and automated high-throughput drug sensitivity and resistance testing (DSRT) for individualized treatment within the time available for clinical application.

Using curated reference databases of drug sensitivity in GBM and healthy bone marrow cells, we identified individualized treatment options in all patients. Individualized treatment options could be selected from FDA-approved drugs from a variety of different drug classes in all cases.

In recGBM, GSC cultures could successfully be established in the majority of patients. The individual cultures displayed intertumoral heterogeneity in their in vitro and in vivo behavior. Within a time frame for clinical application, we could perform DSRT in 50% of recGBM patients. The DSRT revealed a remarkable intertumoral heterogeneity in sensitivity to anticancer drugs in recGBM that could allow tailored therapeutic options for functional precision medicine.

This study demonstrates the feasibility of a bed-to-bench-to-bed clinical translational protocol in recGBM utilizing automated drug screening and autologous recGSC cultures for individualized therapy selection. From surgical biopsies in recGBM, we were able to expand GSCs form 70% of the patients and generate adequate cell numbers from 50% within a clinically acceptable time period. The DSRT revealed patient-specific drug vulnerabilities to single drugs, as well as classes of drugs, with the potential for fast clinical translation. The sensitivity profiles covered a range of drug classes and molecular targets that demonstrated a remarkable intertumoral heterogeneity in drug sensitivity patterns in recGSCs.