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| Status |
Public on Oct 20, 2020 |
| Title |
A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Agilent] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Abstract. Background: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Differential gene expression classifies IDH-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of the proto-oncogene tyrosine-protein kinase SRC, is one of many therapeutics that, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib therapy and could hence be used for patient enrichment strategies in clinical trials. Methods: We carried out in silico analyses of the TCGA glioblastoma gene expression data and single-cell RNA-Seq data, in combination with in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors with complimentary gene expression profiling and immunohistochemistry analyses of tumor samples. Results: Patients suffering from the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling, and accordingly, mesenchymal cells were more sensitive to SRC inhibition by dasatinib compared to proneural and classical cells. Furthermore, SERPINH1, a heat-shock protein relevant in many cancer entities, was shown to highly correlate with dasatinib response and with the mesenchymal subtype. Notably, SRC phosphorylation status was not able to reliably predict response to dasatinib treatment. Conclusion: This work highlights the need for rational methods of patient selection for clinical trials, and retrospectively sheds light on a possible gene expression subtype-led patient stratification strategy that could have improved the outcome of SRC inhibition in patients and could have implications for future trials.
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| Overall design |
NCH711d and NCH705 cells were inhibited in three independent experiments with DMSO and 1µM of Dasatinib. After 4 days, RNA was extracted and checked using the same method outlined earlier.
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| Contributor(s) |
. Alhalabi O, Goidts V |
| Citation(s) |
34232320 |
| Submission date |
Oct 19, 2020 |
| Last update date |
Oct 28, 2021 |
| Contact name |
Obada Taleb Alhalabi |
| E-mail(s) |
obadath@hotmail.com
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| Organization name |
German Cancer Research Center DKFZ
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| Department |
Brain Tumor Translational Targets
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| Lab |
Violaine Goidts
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| Street address |
Im Neuenheimer Feld 580 - TP3
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| City |
Heidelberg |
| ZIP/Postal code |
69120 |
| Country |
Germany |
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| Platforms (1) |
| GPL21185 |
Agilent-072363 SurePrint G3 Human GE v3 8x60K Microarray 039494 [Probe Name Version] |
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| Samples (11)
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| This SubSeries is part of SuperSeries: |
| GSE159609 |
A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma |
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| Relations |
| BioProject |
PRJNA669848 |
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