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BMC Cancer. 2019 Jun 25;19(1):628. doi: 10.1186/s12885-019-5861-4.

Intertumoral heterogeneity in patient-specific drug sensitivities in treatment-naïve glioblastoma.

Author information

1
Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway. erlend.skaga@gmail.com.
2
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317, Oslo, Norway. erlend.skaga@gmail.com.
3
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Tukholmankatu 8, 00290, Helsinki, Finland.
4
Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway.
5
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317, Oslo, Norway.
6
National Institute for Health and Welfare, Genomics and Biomarkers Unit, P.O. Box 30, FI-00271, Helsinki, Finland.
7
Department of Neurosurgery, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Topeliuksenkatu 5, 00260, Helsinki, Finland.

Abstract

BACKGROUND:

A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear.

METHODS:

We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation.

RESULTS:

Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses.

CONCLUSIONS:

This study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine.

KEYWORDS:

Drug sensitivity; Functional precision medicine; Glioblastoma; Glioblastoma stem cells; High-throughput drug screening; Individualized medicine

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