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A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Agilent]

ABSTRACT: A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Agilent]

PROVIDER: PRJNA669848 | ENA |

REPOSITORIES: ENA

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A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Agilent]

Project description: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.

2020-10-20 | GSE159605 | GEO

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Illumina]

2020-10-20 | GSE159607 | GEO

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma

Project description:A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma

| PRJNA669855 | ENA

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Illumina]

Project description:A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma [Illumina]

| PRJNA670013 | ENA

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-20 | GSE159609 | GEO

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

Project description: Not available

| S-EPMC8730774 | biostudies-literature

Gene expression profiles of dasatinib-resistant and dasatinib-sensitive pancreatic cancer cell lines

Project description:Gene profiles from three dasatinib-resistant and three dasatinib-sensitive pancreatic cancer cell lines were compared by microarray analysis.

2015-02-24 | GSE59357 | GEO

Gene expression profiles of dasatinib-resistant and dasatinib-sensitive pancreatic cancer cell lines

Project description:Gene profiles from three dasatinib-resistant and three dasatinib-sensitive pancreatic cancer cell lines were compared by microarray analysis. RNA from three dasatinib-resistant (MiaPaCa2, Panc1, SU8686) and three dasatinib-sensitive (Panc0504, Panc0403, Panc1005) pancreatic cancer cell lines were extracted. Biological triplicates were employed for each cell line. Complementary DNA microarray analysis was performed using Illumina Human HT-12 v4 BeadChip (Illumina, San Diego, CA) at the National University of Singapore Core Facility following the manufacturer’s instructions.

2015-02-24 | E-GEOD-59357 | biostudies-arrayexpress

Gene expression signatures of dasatinib-treated chronic myeloid leukemia patients with resistance to imatinib

Project description:Dasatinib has demonstrated efficacy in patients with chronic-phase chronic myeloid leukemia (CML) who had resistance or intolerance to imatinib. However, some patients also develop resistance or intolerance to dasatinib. To identify potential molecular pathways involved in primary resistance to dasatinib in CML, we analyzed gene expression profiles of mononuclear cells of 7 imatinib-resistant patients, collected before and after 1-year dasatinib treatment. Large-scale gene expression was measured with Agilent microarrays covering protein-coding genes and long (>200 nt) noncoding RNAs (lncRNAs). Sets of genes and lncRNAs significantly differentially expressed (>1.5 fold-change; q value ≤10%) were identified. Ingenuity Pathway Analysis pointed to a number of functions, canonical pathways and gene networks that were significantly enriched with differentially expressed genes. In addition to protein-coding genes, lncRNAs have been recently implicated in pathways leading to tumorigenesis. Our data point to new possible regulatory elements involved in dasatinib resistance in CML.

2013-07-31 | GSE33290 | GEO

Dasatinib enhances anti-tumor efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

Project description:CD19-targeted Chimeric antigen receptor T cells (CART) cells have shown remarkable promise in various B cell malignancies. Sustained tonic signaling and antigen exposure drives CART cell differentiation and exhaustion, which limits the therapeutic potency and persistence of CART cells and is a major cause of CD19-expressing leukemia relapse after CD19-targeted CART cells treatment in ALL. Here, we systematically screened FDA approved tyrosine kinase inhibitors, and identified dasatinib as the best candidate to prevent or reverse both CD28/CART and 4-1BB/CART cells from differentiation and exhaustion during ex vivo expansion, which enhanced the therapeutic efficacy and in vivo persistence. Using RNA-seq, we identified the differentially expressed genes between dasatinib treated group and Nalm6 stimulated group, and found that memory-associated transcription factors TCF7 and naive/memory-associated cell surface marker CCR7 were upregulated, whereas exhaustion-related regulators (NR4A1, BATF3, ATF4 and FOS) and inhibitory receptors (PD1, LAG3) were down-regulated in dasatinib treated CAR T cells. Moreover, T cell activation associated signaling pathways (T cell receptor, Jak-STAT, MAPK and PI3K-Akt) which were upregulated in Nalm6 stimulated CART cells, showed fundamental downregulation in dasatinib treated CART cells. These findings imply that dasatinib played important roles in CART cell differentiation and exhaustion by inhibition of T cell activation pathways.

2021-06-03 | GSE151774 | GEO

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