Abstract
BackgroundDespite 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.ResultsFrom ten patients undergoing surgery for recGBM, we established individual cell cultures and characterized the GSCs by functional assays. 7/10 GSC cultures could be serially expanded. The individual GSCs displayed intertumoral differences in their proliferative capacity, expression of stem cell markers and variation in their in vitro and in vivo morphology. We defined a time frame of 10 weeks from surgery to complete the entire pre-clinical work-up; establish individualized GSC cultures, evaluate drug sensitivity patterns of 525 anticancer drugs, and identify options for individualized treatment. Within the time frame for clinical translation 5/7 cultures reached sufficient cell yield for complete drug screening. The DSRT revealed significant intertumoral heterogeneity to anticancer drugs (p < 0.0001). 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.ConclusionsIn 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.
Highlights
Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clini‐ cal trials investigate treatment effects at population level
Recurrent GBM patient characteristics The recurrent glioblastoma stem cell (GSC) cultures were established from ten patients undergoing surgery for recurrent GBM (recGBM). 9/10
Preclinical characterization of autologous recurrent GSC cultures To allow for a wide drug screen, the drug sensitivity and resistance testing (DSRT) required 107 cells
Summary
Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clini‐ cal trials investigate treatment effects at population level. In the newly diagnosed GBM, sphere-forming glioblastoma stem cells (GSCs) derived from tumor biopsies is a well-studied and relevant model system of the treatment-naïve disease [6,7,8,9]. The biology of the recurrent disease, which is the disease the patients succumb to, remains inadequately described. This leads to a clinical translational gap, as early phase clinical trials in GBM mostly recruit patients with recurrent disease while the foundation of these new treatments almost exclusively are based on treatment-naïve primary GBM models [10]
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