Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA108655 | ENA |
REPOSITORIES: ENA
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Project description:Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, mitosis and cytokinesis were inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. Chromatin-immunoprecipitation-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. Collectively, our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy. ChIP-chip analysis for H3K9K14ac in A549, H1299 and CL1-1 lung cancer cells treated with 2.5 uM histone deacetylase inhibitor, OSU-HDAC-44, for 2 hours.
2010-12-22 | E-GEOD-20304 | biostudies-arrayexpress
Project description:Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment (TME). Actionable mechanisms that rescue the effector activity of anti-tumor T cells in a metabolically restricted TME remain elusive. Here, we report that the Sirtuin-2 (Sirt2) protein deacetylase functions as a master metabolic checkpoint that inhibits T cell metabolic fitness and impairs T cell effector functions and anti-tumor immunity. Mechanistically, Sirt2 suppresses glycolysis and oxidative-phosphorylation (OxPhos) by deacetylating key enzymes involved in glycolysis, tricarboxylic acid (TCA)-cycle, fatty acid oxidation (FAO) and glutaminolysis. Accordingly, Sirt2-deficient T cells exhibit a hyper-metabolic activity with increased glycolysis and OxPhos, resulting in enhanced proliferation and effector functions at tumor beds and subsequently exhibiting superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human lung tumor-infiltrating lymphocytes (TILs) with these superior metabolic fitness and enhanced effector functions. Furthermore, upregulation of Sirt2 expression in human TILs negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer (NSCLC). Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
2020-06-16 | PXD019763 | Pride
Project description:This study investigates the safety/toxicity and potential anti-tumor activity of sequential administration of nivolumab and escalating doses of the mTOR inhibitor ABI-009 in advanced Ewing’s sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors
| 2247222 | ecrin-mdr-crc
Project description:Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.
2017-04-22 | GSE98048 | GEO
Project description:In order to ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the anti-tumour effects of Trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via MTT assay. TSA and vorinostat both displayed strong anti-tumor activities in a proportion of NSCLC cell lines, and suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified NCI program. In addition, pathway analysis was performed with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine (SVM) algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the SVM model was validated by an additional seven cell lines, resulting in a prediction value of 100% in respect to determining response to TSA. Our results suggested that [1] HDAC inhibitors may be promising anticancer drugs to NSCLC, and [2] the nine gene classifer is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients. training sample set:; GSM94303 PC9; GSM94304 PC7; GSM94305 PC14; GSM94306 A549; GSM94308 LK2; GSM94313 RERF LC-KJ; GSM94314 RERF LC-MS; GSM94315 RERF-LC-AI; GSM94316 PC-1; GSM94317 PC-3; GSM94319 PC-10; GSM94323 ABC-1; GSM94324 EBC-1; GSM94325 LC2/ad; GSM94328 SQ-5; GSM94329 QG-56; test sample set:; GSM94307 LU65; GSM94326 LC1/sq; GSM94327 LC-1F; GSM254967 LCOK; GSM254968 LCD; GSM254969 H1650; GSM254970 H1975 Experiment Overall Design: gene expression analyis in lung cancer cell lines
2008-06-11 | E-GEOD-10089 | biostudies-arrayexpress
Project description:This study is an open label non randomized study of hydroxychloroquine (HCQ) with histone deacetylase (HDAC) inhibitor Vorinostat in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and to evaluate the safety and antitumor activity of this drug combination.
| 2081555 | ecrin-mdr-crc
Project description:Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. 6 Kras-mutant/p53-deficient lung tumors T cells and macrophages were analyzed wth Nanostring mouse PanCancer immune module
2017-04-22 | GSE98044 | GEO
Project description:The model predicts the inhibitory potential of small molecules against Histone deacetylase 3 (HDAC3), a relevant human target for cancer, inflammation, neurodegenerative diseases and diabetes. The authors have used a dataset of 1098 compounds from ChEMBL and validated the model using the benchmark MUBD-HDAC3.
Model Type: Predictive machine learning model.
Model Relevance: Probability that the molecule is a HDAC3 inhibitor
Model Encoded by: Sarima Chiorlu (Ersilia)
Metadata Submitted in BioModels by: Zainab Ashimiyu-Abdusalam
Implementation of this model code by Ersilia is available here:
https://github.com/ersilia-os/eos1n4b
2024-08-06 | MODEL2406210001 | BioModels
Project description:Histone deacetylase (HDAC) inhibitors are part of a new generation of epigenetic drugs for cancer treatment. It is known that histone acetylation plays a key role in controlling essential chromosome functions, including gene regulation, and this process has been linked with cancer development and progression. Better understanding of molecular mechanisms involving HDAC inhibitors is needed for the design of new targeted drugs, and also to evaluate the effectiveness of current treatments. In this study, an untargeted metabolomics approach was used to identify intracellular metabolite deregulation after treating cancer cell lines with the HDAC inhibitor HC-Toxin. Metabolomics analysis was performed using high resolution mass spectrometry, in combination with univariate and multivariate statistics and pathway analysis. HDAC inhibition showed highly specific metabolic changes in cancer cell lines compared to non-cancerous cells. In particular, N-acetyl-L-cysteine, N-acetylmethionine, and N-acetyl-L-carnitine showed a dose dependent change. Moreover, pathways controlling protein biosynthesis, as well as tryptophan, cysteine and methionine metabolism were significantly altered by HDAC inhibition. This study illustrates that HDAC inhibition has multiple effects on different metabolic pathways and our results can be extrapolated to inform on the molecular transitions in human cells.
2022-05-04 | MTBLS682 | MetaboLights
Project description:Copy number profiling of 92 human lung tumors on Affymetrix 100K SNP arrays was conducted in order to assess the interaction of common genomic alterations with response to targeted anti-cancer therapeutics. Class 1 phosphatidylinositol 3' kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here we investigate biomarker strategies for PI3K pathway inhibitors in non-small-cell lung cancer (NSCLC). Molecular profiling of NSCLC tumor samples showed that copy number gains in PIK3CA and total loss of PTEN protein were common in squamous cell carcinoma samples, whereas LKB1 loss and mutations in KRAS and EGFR were common in adenocarcinomas. A panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers. Cell lines harboring pathway alterations (RTK activation, PI3K mutation or amplification, PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a MEK inhibitor had greater effects on cell viability than PI3K inhibition alone. CONCLUSIONS: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with non-squamous NSCLC patient populations. Lung tumors were profiled on Affymetrix GeneChip Mapping 100K Set Arrays Tumor samples were profiled for copy number without any treatment of the tumor.
2013-01-10 | E-GEOD-39793 | biostudies-arrayexpress