Effect of medication with Belinostat and Dasatinib on gene expression during MGG8, Glioblastoma Stem cell
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ABSTRACT:
PROVIDER: PRJNA1007575 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25706662_1.fastq.gz | Fastqsanger.gz | |||
| SRR25706662_2.fastq.gz | Fastqsanger.gz | |||
| SRR25706663_1.fastq.gz | Fastqsanger.gz | |||
| SRR25706663_2.fastq.gz | Fastqsanger.gz | |||
| SRR25706664_1.fastq.gz | Fastqsanger.gz |
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Project description:To evaluate the effects of selected therapeutic drugs focusing on gene expression, we administered drugs to MGG8 GSCs, extracted RNA, and compared them.
2024-08-01 | GSE241247 | GEO
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
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 | GSE159607 | GEO
Project description:An effective long-term inhibition of multiple DNA repair signals is required to design a novel and effective therapeutic for glioblastoma (GBM), a highly DNA repair ‘addicted’ cancer. AsiDNA, a double-strand DNA break (DSB) mimetic, is an innovative approach that shuts down the entire DNA repair system in cancer cells by sequestering DSB repair factors. We showed that inhibition of class I histone deacetylases (HDACs) dislodges repair factors from sites of DNA damage. We therefore tested whether AsiDNA and pan HDAC inhibitor Belinostat combination can impart a chromatin-based long-term DNA damage and impair DNA repair in GBM cells. We performed mass spectrometry with chromatin isolated from AsiDNA and Belinostat and found that Belinostat reduces histone H1.2 levels. To this end, we assessed whether AsiDNA and Belinostat alter histone H1.2 occupancy genome-wide. In order to understand the long-term effects of AsiDNA on DNA repair, we treated U87 cells with AsiDNA for 6 days followed by 6 days recovery from the drug. We used this protocol to create long-term AsiDNA treated cells (LTAU87) according to the clinical trial protocol. We performed NicE-seq with LTAU87 cells and MTU87 (mock treated U87; control) in the presence or absence of belinostat treatment in order to address whether they alter the global chromatin structure.
2024-05-13 | GSE266621 | GEO
Project description:An effective long-term inhibition of multiple DNA repair signals is required to design a novel and effective therapeutic for glioblastoma (GBM), a highly DNA repair ‘addicted’ cancer. AsiDNA, a double-strand DNA break (DSB) mimetic, is an innovative approach that shuts down the entire DNA repair system in cancer cells by sequestering DSB repair factors. We showed that inhibition of class I histone deacetylases (HDACs) dislodges repair factors from sites of DNA damage. We therefore tested whether AsiDNA and pan HDAC inhibitor Belinostat combination can impart a chromatin-based long-term DNA damage and impair DNA repair in GBM cells. In order to understand the long-term effects of AsiDNA on DNA repair, we treated U87 cells with AsiDNA for 6 days followed by 6 days recovery from the drug. We used this protocol to create long-term AsiDNA treated cells (LTAU87) according to the clinical trial protocol. We performed RNA-Seq with LTAU87 cells and MTU87 (mock treated U87; control) in the presence and absence of belinostat.
2024-05-13 | GSE266620 | GEO
Project description:An effective long-term inhibition of multiple DNA repair signals is required to design a novel and effective therapeutic for glioblastoma (GBM), a highly DNA repair ‘addicted’ cancer. AsiDNA, a double-strand DNA break (DSB) mimetic, is an innovative approach that shuts down the entire DNA repair system in cancer cells by sequestering DSB repair factors. We showed that inhibition of class I histone deacetylases (HDACs) dislodges repair factors from sites of DNA damage. We therefore tested whether AsiDNA and pan HDAC inhibitor Belinostat combination can impart a chromatin-based long-term DNA damage and impair DNA repair in GBM cells. We performed mass spectrometry with chromatin isolated from AsiDNA and Belinostat and found that Belinostat reduces histone H1.2 levels. To this end, we assessed whether AsiDNA and Belinostat alter histone H1.2 occupancy genome-wide. In order to understand the long-term effects of AsiDNA on DNA repair, we treated U87 cells with AsiDNA for 6 days followed by 6 days recovery from the drug. We used this protocol to create long-term AsiDNA treated cells (LTAU87) according to the clinical trial protocol. We performed H1.2 ChIP-Seq with LTAU87 cells and MTU87 (mock treated U87; control) in the presence and absence of belinostat in order to address whether they alter the global chromatin structure.
2024-05-13 | GSE266619 | GEO
Project description:Background: Glioblastoma (GB) is the most common primary malignancy of the central nervous system. It can be classified into proneural (PN), mesenchymal (MES) and classical (CL) based on transcriptomics. Due to increased resistance against targeted therapies, such as the PN subtype and dasatinib, identification of combination therapies is of great interest. Methods: Proteomics and phosphoproteomics data were collected from dasatinib inhibited glioblastoma stem cells (GSCs). Additionally, a pooled shRNA loss-of-function viability screen was utilized to identify genes whose knockdown sensitizes GSCs to dasatinib. These data, along with existing transcriptomics data, were computationally integrated using a novel modification of the SamNet algorithm (SamNet 2.0) for network flow learning to identify potential combination therapies. In vitro viability assays were used to verify synergy of potential combinations. Results: Using omics data and the pooled shRNA screen, the cell cycle protein WEE1 was identified as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data.
2026-01-12 | PXD039264 | Pride
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
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
Project description:Determine whether AsiDNA and belinostat alter chromatin accessbility genome-wide in glioblastoma cells. [NicE-Seq]
| PRJNA1107962 | ENA