Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Ioannis Ntafoulis; Anne Kleijn; Jie Ju; Kevin Jimenez-Cowell; Federica Fabro; Michelle Klein; Romain Tching Chi Yen; Rutger K. Balvers; Yunlei Li; Andrew P. Stubbs; Trisha V. Kers; Johan M. Kros; Sean E. Lawler; Laurens V. Beerepoot; Andreas Kremer; Ahmed Idbaih; Maite Verreault; Annette T. Byrne; Alice C. O’Farrell; Kate Connor; Archita Biswas; Manuela Salvucci; Jochen H.M. Prehn; Diether Lambrechts; Gonca Dilcan; Francesca Lodi; Ingrid Arijs; Martin J. van den Bent; Clemens M.F. Dirven; Sieger Leenstra; Franck Bielle; Emie Quissac; Jane Cryan; Francesca Brett; Alan Beausang; Orna Bacon; Steve MacNally; Philip O’Halloran; James Clerkin; Martine L.M. Lamfers

doi:10.1038/s41416-023-02402-y

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Ioannis Ntafoulis, Anne Kleijn, Jie Ju, Kevin Jimenez-Cowell, Federica Fabro, Michelle Klein, Romain Tching Chi Yen, Rutger K. Balvers, Yunlei Li, Andrew P. Stubbs, Trisha V. Kers, Johan M. Kros, Sean E. Lawler, Laurens V. Beerepoot, Andreas Kremer, Ahmed Idbaih, Maite Verreault, Annette T. Byrne, Alice C. O’Farrell, Kate ConnorArchita Biswas, Manuela Salvucci, Jochen H.M. Prehn, Diether Lambrechts, Gonca Dilcan, Francesca Lodi, Ingrid Arijs, Martin J. van den Bent, Clemens M.F. Dirven, Sieger Leenstra, Franck Bielle, Emie Quissac, Jane Cryan, Francesca Brett, Alan Beausang, Orna Bacon, Steve MacNally, Philip O’Halloran, James Clerkin, Martine L.M. Lamfers^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1327-1338
Number of pages	12
Journal	British Journal of Cancer
Volume	129
Issue number	8
DOIs	https://doi.org/10.1038/s41416-023-02402-y
Publication status	Published - 12 Oct 2023

Bibliographical note

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Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkersFinal published version, 2.23 MBLicence: CC BY

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Ntafoulis, I., Kleijn, A., Ju, J., Jimenez-Cowell, K., Fabro, F., Klein, M., Chi Yen, R. T., Balvers, R. K., Li, Y., Stubbs, A. P., Kers, T. V., Kros, J. M., Lawler, S. E., Beerepoot, L. V., Kremer, A., Idbaih, A., Verreault, M., Byrne, A. T., O’Farrell, A. C., ... Lamfers, M. L. M. (2023). Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers. British Journal of Cancer, 129(8), 1327-1338. https://doi.org/10.1038/s41416-023-02402-y

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title = "Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers",

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.",

author = "Ioannis Ntafoulis and Anne Kleijn and Jie Ju and Kevin Jimenez-Cowell and Federica Fabro and Michelle Klein and {Chi Yen}, {Romain Tching} and Balvers, {Rutger K.} and Yunlei Li and Stubbs, {Andrew P.} and Kers, {Trisha V.} and Kros, {Johan M.} and Lawler, {Sean E.} and Beerepoot, {Laurens V.} and Andreas Kremer and Ahmed Idbaih and Maite Verreault and Byrne, {Annette T.} and O{\textquoteright}Farrell, {Alice C.} and Kate Connor and Archita Biswas and Manuela Salvucci and Prehn, {Jochen H.M.} and Diether Lambrechts and Gonca Dilcan and Francesca Lodi and Ingrid Arijs and {van den Bent}, {Martin J.} and Dirven, {Clemens M.F.} and Sieger Leenstra and Franck Bielle and Emie Quissac and Jane Cryan and Francesca Brett and Alan Beausang and Orna Bacon and Steve MacNally and Philip O{\textquoteright}Halloran and James Clerkin and Lamfers, {Martine L.M.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = oct,

day = "12",

doi = "10.1038/s41416-023-02402-y",

language = "English",

volume = "129",

pages = "1327--1338",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "8",

}

Ntafoulis, I , Kleijn, A , Ju, J, Jimenez-Cowell, K, Fabro, F , Klein, M, Chi Yen, RT, Balvers, RK , Li, Y , Stubbs, AP, Kers, TV, Kros, JM, Lawler, SE, Beerepoot, LV, Kremer, A, Idbaih, A, Verreault, M, Byrne, AT, O’Farrell, AC, Connor, K, Biswas, A, Salvucci, M, Prehn, JHM, Lambrechts, D, Dilcan, G, Lodi, F, Arijs, I, van den Bent, MJ, Dirven, CMF , Leenstra, S, Bielle, F, Quissac, E, Cryan, J, Brett, F, Beausang, A, Bacon, O, MacNally, S, O’Halloran, P, Clerkin, J & Lamfers, MLM 2023, 'Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers', British Journal of Cancer, vol. 129, no. 8, pp. 1327-1338. https://doi.org/10.1038/s41416-023-02402-y

TY - JOUR

T1 - Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

AU - Ntafoulis, Ioannis

AU - Kleijn, Anne

AU - Ju, Jie

AU - Jimenez-Cowell, Kevin

AU - Fabro, Federica

AU - Klein, Michelle

AU - Chi Yen, Romain Tching

AU - Balvers, Rutger K.

AU - Li, Yunlei

AU - Stubbs, Andrew P.

AU - Kers, Trisha V.

AU - Kros, Johan M.

AU - Lawler, Sean E.

AU - Beerepoot, Laurens V.

AU - Kremer, Andreas

AU - Idbaih, Ahmed

AU - Verreault, Maite

AU - Byrne, Annette T.

AU - O’Farrell, Alice C.

AU - Connor, Kate

AU - Biswas, Archita

AU - Salvucci, Manuela

AU - Prehn, Jochen H.M.

AU - Lambrechts, Diether

AU - Dilcan, Gonca

AU - Lodi, Francesca

AU - Arijs, Ingrid

AU - van den Bent, Martin J.

AU - Dirven, Clemens M.F.

AU - Leenstra, Sieger

AU - Bielle, Franck

AU - Quissac, Emie

AU - Cryan, Jane

AU - Brett, Francesca

AU - Beausang, Alan

AU - Bacon, Orna

AU - MacNally, Steve

AU - O’Halloran, Philip

AU - Clerkin, James

AU - Lamfers, Martine L.M.

PY - 2023/10/12

Y1 - 2023/10/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85168623419&partnerID=8YFLogxK

U2 - 10.1038/s41416-023-02402-y

DO - 10.1038/s41416-023-02402-y

M3 - Article

C2 - 37620410

AN - SCOPUS:85168623419

SN - 0007-0920

VL - 129

SP - 1327

EP - 1338

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 8

ER -

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Abstract

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