Reversal of Cancer Gene Expression Identifies Repurposed Drugs for Diffuse Intrinsic Pontine Glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193855 | GEO | 2022/10/20
REPOSITORIES: GEO
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Project description:<p>Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.</p>
| phs000900 | dbGaP
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy. A microarray study using genomic DNA from different DLBCL cell lines before any treatment. Two to four biological replicates by cell line. The HELP data wil be used to find genes hypermethylated in resistant cell lines compared to sensitive cell lines to doxorubicin and other drugs.
2012-07-29 | E-GEOD-31101 | biostudies-arrayexpress
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2M-bM-^@M-^Y-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2M-bM-^@M-^Y-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2M-bM-^@M-^Y-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy. A microarray study using double-stranded cDNA from different DLBCL cell lines before any treatment. Two biological replicates by cell line. The gene expression will be used to find gene expression signatures between sensitive and resistant cell lines to chemotherapeutics.
2012-07-29 | E-GEOD-28744 | biostudies-arrayexpress
Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ?0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. To develop gene expression signatures for in vitro drug response and other phenotypes. Profiling was done on 68 NSCLC cell lines and 2 HBEC-KT cell lines (normal lung cells immortalized with CDK4 and hTERT).
2012-10-25 | E-GEOD-32989 | biostudies-arrayexpress
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and highly aggressive pediatric tumor. The average survival time after diagnosis is less than one year. Currently, there are no effective treatments. Characteristic of DIPG is a mutation in histone H3 which leads to a substitution of Lysine 27 to Methionine (H3K27M) which deregulates Polycomb Repressive Complex 2 (PRC2), including enzymatic activity of EZH2. Previous studies have shown that inhibition of EZH2 by chemical agents decreases DIPG cell proliferation and inhibits tumor growth in vivo. My thesis project aims to confirm that EZH2 could be a therapeutic target using chemical EZH2 inhibitors, small interfering RNAs and a CRISPR/Cas9 approach in a series of DIPG tumor cell lines and to determine underlying molecular mechanisms of action.
2022-04-01 | PXD017525 | Pride
Project description:We combined a mechanism-based and a cell-based drug screening coupled to a computational analysis, which allowed to identify potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis. This result was achieved by comparing gene-expression signature of lead compounds that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature revealed by RNA-seq.
2021-11-26 | GSE184805 | GEO
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy.
2012-07-30 | GSE31101 | GEO
Project description:Silencing of genes that suppress the malignant phenotype by DNA methylation spurred an interest in the clinical use of epigenetic reprogramming agents. Single therapy is unlikely to be curative in the context of a heterogeneous disease such as Diffuse Large B cell Lymphomas (DLBCL). The combination of DNA demethylating drugs could increase the chance to respond to classical and new treatments. We found that DLBCL cell lines respond heterogeneously to DNA demethylating agents. In sensitive cell lines, 5-aza-2’-deoxycytidine induced a genomic signature similar to that of doxorubicin, the most important drug of the combinatorial chemotherapy regimen for DLBCL treatment. Accordingly, the combination of 5-aza-2’-deoxycytidine and doxorubicin proved to be synergistic in cell killing in vitro and in vivo for DLBCL cell lines individually responsive to these drugs. In doxorubicin resistant cell lines, long-term exposure to low-dose of 5-aza-2’-deoxycytidine induces DNA demethylation and subsequent doxorubicin sensitization in vitro and in vivo. This later effect correlates with SMAD1 demethylation. SMAD1 is epigenetically silenced in doxorubicin-resistant DLBCL cells and DLBCL patients with poor prognostic. In addition, we found that DNA demethylating agents can sensitize primary DLBCL cells to doxorubicin. Primary cells obtained from a DLBCL patient treated with 5-azacytidine shows SMAD1 demethylation and ex vivo sensitization to multiple drugs. Therefore, DNA demethylating drugs can reprogram otherwise resistant DLBCL cells to respond to chemotherapy agents without increasing the toxicity to normal tissues. Our data also indicate that DNA methylation and consequent suppression of SMAD1 expression represent a previously undescribed molecular mechanism of chemoresistance in DLBCL that can be further exploit for therapy.
2012-07-30 | GSE28744 | GEO
Project description:Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. A reverse proteomic approach has identified the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.
2017-11-13 | PXD007765 | Pride
Project description:Motivation and design: Renal tubulointerstitial injury is an important determinant of chronic kidney disease (CKD) progression, yet treatment is limited to renin angiotensin system blockade. Accordingly, we performed global expression profiling in a 2 × 2 factorial design (N = 8 in each group) on RNA extracted from male Col4a3–/– mice and littermate controls on a 129X1/SvJ background at 4 and 7 weeks of age. Col4a3–/– mice have a mutation in the gene encoding the α3 chain of type IV collagen, associated with proteinuria and progressive loss of kidney function. We analyzed expression with Affymetrix GeneChip Mouse Gene 2.0 ST Arrays and derived a novel CKD progression signature based on aging and disease in Col4a3–/– mice. Using our progression signature, we sought to repurpose existing drugs for the treatment of progressive CKD. Results: Computational drug repurposing with the Connectivity Map identified lysine deacetylase inhibitor, vorinostat, as a novel candidate treatment for this murine model of CKD. Treatment with vorinostat attenuated tubulointerstitial injury, fibrosis, and altered inflammation. Vorinostat administration significantly increased the lifespan of Col4a3–/– mice although effects on urinary albumin excretion, plasma creatinine, and blood urea nitrogen were modest. Conclusions: Our data suggest that expression profiling and computational drug repurposing can be used to identify novel drugs that may reverse gene expression changes in experimental CKD. Lysine deacetylase inhibition may be a novel treatment approach to CKD associated with proteinuria and progressive tubulointerstitial injury.
2020-01-31 | GSE137086 | GEO