Functional temozolomide sensitivity testing of patient-specific glioblastoma stem cell cultures is predictive of clinical outcome

Erlend Skaga; Evgeny Kulesskiy; Swapnil Potdar; Ioannis Panagopoulos; Francesca Micci; Iver A Langmoen; Cecilie J Sandberg; Einar O Vik-Mo

doi:10.1016/j.tranon.2022.101535

Functional temozolomide sensitivity testing of patient-specific glioblastoma stem cell cultures is predictive of clinical outcome

Transl Oncol. 2022 Dec:26:101535. doi: 10.1016/j.tranon.2022.101535. Epub 2022 Sep 15.

Authors

Erlend Skaga¹, Evgeny Kulesskiy², Swapnil Potdar², Ioannis Panagopoulos³, Francesca Micci³, Iver A Langmoen⁴, Cecilie J Sandberg⁵, Einar O Vik-Mo⁵

Affiliations

¹ Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway. Electronic address: erlend.skaga@gmail.com.
² Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Tukholmankatu 8, 00290, Helsinki, Finland.
³ Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, P.O. Box 4954 Nydalen, 0424, Oslo, Norway.
⁴ Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317, Oslo, Norway.
⁵ Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway.

Abstract

Serum-free culturing of patient-derived glioblastoma biopsies enrich for glioblastoma stem cells (GSCs) and is recognized as a disease-relevant model system in glioblastoma (GBM). We hypothesized that the temozolomide (TMZ) drug sensitivity of patient-derived GSC cultures correlates to clinical sensitivity patterns and has clinical predictive value in a cohort of GBM patients. To this aim, we established 51 individual GSC cultures from surgical biopsies from both treatment-naïve primary and pretreated recurrent GBM patients. The cultures were evaluated for sensitivity to TMZ over a dosing range achievable in normal clinical practice. Drug efficacy was quantified by the drug sensitivity score. MGMT-methylation status was investigated by pyrosequencing. Correlative, contingency, and survival analyses were performed for associations between experimental and clinical data. We found a heterogeneous response to temozolomide in the GSC culture cohort. There were significant differences in the sensitivity to TMZ between the newly diagnosed and the TMZ-treated recurrent disease (p <0.01). There was a moderate correlation between MGMT-status and sensitivity to TMZ (r=0.459, p=0.0009). The relationship between MGMT status and TMZ efficacy was statistically significant on multivariate analyses (p=0.0051). We found a predictive value of TMZ sensitivity in individual GSC cultures to patient survival (p=0.0089). We conclude that GSC-enriched cultures hold clinical and translational relevance by their ability to reflect the clinical heterogeneity in TMZ-sensitivity, substantiate the association between TMZ-sensitivity and MGMT-promotor methylation status and appear to have a stronger predictive value than MGMT-promotor methylation on clinical responses to TMZ.

Keywords: Drug sensitivity; Glioblastoma; Glioblastoma stem cells; Temozolomide; Tumor heterogeneity.