Gene Re-expression in Calu6 Tumors Following Epigenetic Therapy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE24732 | GEO | 2011/04/01
SECONDARY ACCESSION(S): PRJNA132355
REPOSITORIES: GEO
Similar Datasets
Project description:Transciptional profiling of Calu6 tumors comparing 4 pooled untreated tumors to 5-azacytodine or 5-azacytodine + MS-275 (combined therapy) treated tumors Three-condition experiment, untreated vs. 5-Azacytodine tumors, and untreated vs. 5-azacytodine + MS-275 tumors: 4 pooled untreated tumors; 4 5-Azacytodine treated, 4 5-Azacytodine + MS-275 treated. Study used a loop design with dye-swap.
2011-04-01 | E-GEOD-24732 | biostudies-arrayexpress
Project description:Phase I trial to study the effectiveness of combining MS-275 with isotretinoin in treating patients who have metastatic or advanced solid tumors or lymphomas. MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Isotretinoin may help cancer cells develop into normal cells. MS-275 may increase the effectiveness of isotretinoin by making cancer cells more sensitive to the drug. MS-275 and isotretinoin may also stop the growth of solid tumors or lymphomas by stopping blood flow to the cancer. Combining MS-275 with isotretinoin may kill more cancer cells
| 2011932 | ecrin-mdr-crc
Project description:RATIONALE: MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth.
PURPOSE: This phase I trial is studying the side effects and best dose of MS-275 in treating patients with advanced solid tumors or lymphoma.
| 2006457 | ecrin-mdr-crc
Project description:Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrate that delivery of class I histone deacetylase inhibitor, MS-275, promotes sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We find that MS-275 alters the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ dendritic cells and depletion of regulatory T cells. Activated endogenous CD8+ T cell responses against non-target tumor antigens was critically required for the prevention of tumor recurrence. Importantly, MS-275 alters the immunodominance hierarchy by directing epitope spreading towards endogenous retroviral tumor-associated antigen, p15E. Our data suggest that MS-275 multi-mechanistically improves epitope spreading to promote long-term clearance of solid tumors.
2021-07-03 | GSE179337 | GEO
Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation. We used whole transcriptome arrays (Clariom D) to determine the effect of MS-275 on exhausted T cells in ACT+/-MS-275-treated mice
2023-07-29 | GSE238222 | GEO
Project description:Part I - SI-NET tumors High Resolution Isoelectric Focusing (HiRIEF) LC-MS and relative quantification by iTRAQ 8-plex was used to analyze 14 small intestinal neuroendocrine tumors (SI-NETs). The data was obtained from two separate TMT10plex sets and linked by a single internal pooled standard. The internal pooled standard was made by combining equal aliquots of the tryptic peptide mixtures from each of the 14 tissue samples. iTRAQ set1 was composed of 7 SI-NET samples, all from different individuals, and internal pooled standard labelled as follows: Channel 113 (sample Screen-1 with liver metastasis), Channel 114 (sample Screen-8 with liver metastasis), Channel 115 (sample Screen-3 with liver metastasis), Channel 116 (sample Screen-2 with liver metastasis), Channel 117 (sample Screen-5 no liver metastasis), Channel 118 (sample Screen-4 no liver metastasis), Channel 119 (sample Screen-10 no liver metastasis), Channel 121 (internal pooled standard). iTRAQ set2 was composed of 7 SI-NET samples, all from different individuals, and internal pooled standard labelled as follows: Channel 113 (sample Screen-7 with liver metastasis), Channel 114 (sample Screen-11 with liver metastasis), Channel 115 (sample Screen-13 with liver metastasis), Channel 116 (sample Screen-6 no liver metastasis), Channel 117 (sample Screen-12 no liver metastasis), Channel 118 (sample Screen-9 no liver metastasis), Channel 119 (sample Screen-14 no liver metastasis), Channel 121 (internal pooled standard). Part II - time course profiling in cell lines High Resolution Isoelectric Focusing (HiRIEF) LC-MS and relative quantification by TMT 10-plex was used to analyze cellular response to the neddylation inhibitor pevonedistat (MLN4924) at different timepoints in two SI-NET (small intestinal neuroendocrine tumors) cell lines. The data was obtained from two separate TMT 10-plex experiments. TMT set1 includes a time course experiment upon pevonedistat treatment of CNDT2 cells with harvests at 2h, 6h, 12h and 24h after treatment as well as of untreated control cells. Isobaric tag labelling of peptide samples with TMT10plex was used as follows. Biological duplicate controls (TMT channels 126, 127N), duplicate 2h (127C, 128N), duplicate 6h (128C, 129N), duplicate 12h (129C, 130N) and duplicate 24h (130C, 131) samples were employed. TMT set2 includes a time course experiment upon pevonedistat treatment of HC45 cells with harvests at 2h, 6h, 12h and 24h after treatment as well as of untreated control cells. Isobaric tag labelling of peptide samples with TMT10plex was used as follows. Biological duplicate controls (TMT channels 126, 127N), duplicate 2h (127C, 128N), duplicate 6h (128C, 129N), duplicate 12h (129C, 130N) and duplicate 24h (130C, 131) samples were employed.
2020-12-09 | PXD009877 | Pride
Project description:Toxoplasma gondii is a ubiquitous apicomplexan parasite of mammals and birds and an important pathogen of humans. IFN-g is the major mediator of host resistance against T. gondii but intriguingly, parasite-infected host cells including macrophages are severely impaired to respond to IFN-g due to defective transcriptional activation of target genes. Here, we tested the possibility that the impaired responsiveness of T. gondii-infected macrophages to IFN-g can be restored by inhibiting histone deacetylases (HDACs) using the class I-specific inhibitor MS-275. Treatment of RAW264.7 cells with MS-275 indeed increased MHC class II surface expression in infected and non-infected cells and largely abolished the inhibition of IFN-g-regulated MHC class II expression exerted by T. gondii. Genome-wide transcriptome profiling revealed that MS-275 increased mean mRNA levels of IFN-g-regulated genes particularly in non-infected macrophages. Transcript levels of 33% of IFN-g secondary response genes but only those of a few primary response genes were also increased by MS-275 in T. gondii-infected cells. Importantly, the unresponsiveness of parasite-infected cells to IFN-g was however not abolished by MS-275. Furthermore, MS-275 also up-regulated several anti-inflammatory cytokines or signaling molecules in T. gondii-infected macrophages. It additionally regulated expression of more than 2500 genes in non-infected macrophages expression of which was surprisingly counteracted by prior infection with T. gondii. FACS analysis and immunofluorescence microscopy revealed that MS-275 did not considerably diminish the number of parasite-positive cells or the intracellular replication in macrophages stimulated or not with IFN-g. Thus, a supportive therapy using MS-275 appears inappropriate for treatment of toxoplasmosis.
2017-02-10 | GSE90478 | GEO
Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.
2015-04-29 | E-GEOD-57130 | biostudies-arrayexpress
Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting.
2015-04-29 | GSE57130 | GEO
Project description:Because insufficiency of the Runt-related transcription factor 2 (Runx2) limits skeletal growth, there is a great deal of effort to activate Runx2 for clinical use. In this study, we found that MS-275, the class I-specific HDAC inhibitor, activates Runx2 both transcriptionally and translationally. Therefore, we performed NGS analysis to gain accurate patterns of gene expression in mouse calvaria tissue through MS-275 administration. As a result, we could get insight that treatment of MS-275 increases genes related with osteoblast differentiation and cell proliferation, and decreases genes in field of causing apoptosis.
2017-09-24 | GSE87608 | GEO