학술논문
Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers
Document Type
Original Paper
Author
Ntafoulis, Ioannis; Kleijn, Anne; Ju, Jie; Jimenez-Cowell, Kevin; Fabro, Federica; Klein, Michelle; Chi Yen, Romain Tching; Balvers, Rutger K.; Li, Yunlei; Stubbs, Andrew P.; Kers, Trisha V.; Kros, Johan M.; Lawler, Sean E.; Beerepoot, Laurens V.; Kremer, Andreas; Idbaih, Ahmed; Verreault, Maite; Byrne, Annette T.; O’Farrell, Alice C.; Connor, Kate; Biswas, Archita; Salvucci, Manuela; Prehn, Jochen H. M.; Lambrechts, Diether; Dilcan, Gonca; Lodi, Francesca; Arijs, Ingrid; van den Bent, Martin J.; Dirven, Clemens M. F.; Leenstra, Sieger; Lamfers, Martine L. M.
Source
British Journal of Cancer. 129(8):1327-1338
Subject
Language
English
ISSN
0007-0920
1532-1827
1532-1827
Abstract
Background: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ).Methods: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data.Results: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets.Conclusion: GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.