Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers.
Humans
Temozolomide
/ pharmacology
Glioblastoma
/ drug therapy
Dacarbazine
/ pharmacology
Drug Evaluation, Preclinical
Glioma
Biomarkers
DNA
/ therapeutic use
Brain Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ genetics
Antineoplastic Agents, Alkylating
/ pharmacology
Cell Line, Tumor
Tumor Microenvironment
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
08
12
2022
accepted:
10
08
2023
revised:
13
07
2023
medline:
23
10
2023
pubmed:
25
8
2023
entrez:
24
8
2023
Statut:
ppublish
Résumé
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). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37620410
doi: 10.1038/s41416-023-02402-y
pii: 10.1038/s41416-023-02402-y
pmc: PMC10575865
doi:
Substances chimiques
Temozolomide
YF1K15M17Y
Dacarbazine
7GR28W0FJI
Biomarkers
0
DNA
9007-49-2
Antineoplastic Agents, Alkylating
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1327-1338Investigateurs
Franck Bielle
(F)
Emie Quissac
(E)
Jane Cryan
(J)
Francesca Brett
(F)
Alan Beausang
(A)
Orna Bacon
(O)
Steve MacNally
(S)
Philip O'Halloran
(P)
James Clerkin
(J)
Informations de copyright
© 2023. The Author(s).
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