Expression profiling PDE4B inhibitor BI 1015550 treatment in a therapeutic Rat Lung Bleomycin Model
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1043126 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26890840.fastq.gz | Fastqsanger.gz | |||
| SRR26890841.fastq.gz | Fastqsanger.gz | |||
| SRR26890842.fastq.gz | Fastqsanger.gz | |||
| SRR26890843.fastq.gz | Fastqsanger.gz | |||
| SRR26890844.fastq.gz | Fastqsanger.gz |
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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressing chronic and fibrotic lung response with poor prognosis. To study the underlying molecular mechanisms of IPF, the rat bleomycin model is commonly used. Intratracheal application of bleomycin is known to induce inflammatory and fibrotic processes in the lung, e.g. infiltratin of inflammatory cells and collagen deposition. Recently, the PDE4B inhibitor BI 1015550 has been reported to prevent a decrease in lung function in patients with IPF. Here we examined the effect of PDE4 inhibitor BI 1015550 in the rat bleomycin model on transcriptional level by RNASeq.
2024-09-17 | GSE248263 | GEO
Project description:Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic
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Project description:BET inhibitors have been tested in several clinical trials, and despite encouraging results from preclinical cancer models, substantial clinical benefit in monotherapy has been limited. An important aspect is the proper translation of preclinical observations into clinical evaluation. The clinical BET inhibitor BI 894999 was tested in mechanistic studies, assessing pathway modulation and rational drug combinations at clinically achievable concentrations. We used NUT carcinoma (NC) cell lines with bona fide oncogenic drivers fusions including BRD4-NUT and BRD3-NUT. Proliferation assays, pathway modulation studies, and in vivo xenografts were performed with BI 894999, in monotherapy, and in combination with the clinical p300/CBP inhibitor CCS1477. Detachment of the BET complex from chromatin in vitro was assessed by LSM immunofluorescence, and by immunohistochemistry in tumour sections. Clinical findings on pathway modulation marker such as HEXIM1 and HIST2H2BF as well as human PK data were back translated to the preclinic setting. The clinical phase I scheduling regimen of 1 week-on (with a loading dose on day 1) and one week-off, derived from modelling of preclinical and clinical data, achieved plasma levels of about 20 nM. This concentration led to the full removal of BRD-NUT from chromatin and resulted in sustained and prolonged PD modulation of HEXIM1 and HIST2H2BF, accompanied with better patient tolerability. Rational combination with the p300/CBP inhibitor CCS1477 led to tumour regression in all three NC xenograft models tested. Preclinical mechanistic studies with the BET inhibitor BI 894999, back translation of clinical PK/PD data, and modelling provided guidance for an optimal clinical schedule. BI 894999 holds significant potential as a combination drug and preclinical data identified p300/CBP inhibitors as highly relevant combination partner for NUT carcinoma and beyond, pending clinical trials.
2022-06-20 | GSE183214 | GEO
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group
2014-10-28 | E-GEOD-48455 | biostudies-arrayexpress
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care.
2014-10-28 | GSE48455 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a complex disease involving various cell types. Macrophages are essential in maintenance of physiological homeostasis, wound repair and fibrosis in the lung. Macrophages play a crucial role in repair and remodeling by altering their phenotype and secretory pattern in response to injury. The secretome of induced pluripotent stem cells (iPSC-cm) attenuates injury and fibrosis in bleomycin injured rat lungs. In the current study, we evaluate the effect of iPSC-cm on interstitial macrophage gene expression and phenotype in bleomycin injured rat lungs in vivo. Â iPSC-cm was intratracheally instilled 7 days after bleomycin induced lung injury and assessed 7 days later and single cell isolation was performed. Macrophages were FACS sorted and microarray analysis was performed. We characterized changes in the rat lung interstitial macrophages using transcriptional profiling.
2017-03-20 | E-MTAB-5619 | biostudies-arrayexpress
Project description:Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment. In vitro combination of both compounds leads to a decrease in S-Phase and to increased apoptosis. In vitro scheduling experiments guided in vivo experiments in disseminated AML mouse models. Co-administration of BI 894999 and volasertib dramatically reduces tumor burden accompanied by long-term survival of tumor-bearing mice and eradication of AML cells in mouse bone marrow. Together, these preclinical findings provide evidence for the strong synergistic effect of BI 894999 and volasertib, warranting future clinical studies in patients with AML to investigate this paradigm.
2018-02-27 | GSE103068 | GEO
Project description:Melanoma patients with high mRNA levels of the HDL receptor SR-BI (SCARB1) reveal poor survival outcome. The aim of the study was to evaluate the role of SR-BI in cancer progression. Therefore, SR-BI was targeted either by siRNA or by using the SR-BI specific lipid transfer inhibitor BLT-1. The SR-BI knockdown specifically revealed reduced protein glycosylation, STAT5 target gene expression and EMT pathway activation. Thus, SR-BI target genes reflect the metastatic phenotype in melanoma cells. We used the transcriptome analysis to compare SR-BI depletion to BLT-1 treatment (which specifically blocks SR-BI mediated lipid transfer) in human melanoma cells.
2018-01-02 | GSE96743 | GEO
Project description:In order to delineate the molecular mechanisms leading to the therapeutic effect of BI 853520 on primary tumor growth, mice harboring 4T1 primary tumors were treated for five days with BI 853520, and RNA extracted from total tumors was subjected to next generation sequencing. Only primary tumors with sufficient RNA quality were included into further analysis (Suppl. Fig. 2A). Gene expression correlation analysis displayed a clear separation of transcriptomic profiles derived from primary tumors of mice treated with BI 853520 or vehicle (Suppl. Fig. 2B). Comparative gene expression analysis of primary tumors of mice treated with BI 853520 versus vehicle control revealed 1293 upregulated and 475 downregulated genes (cutoffs: p-value ≤ 0.05, fold change +/- 1.5). Functional enrichment analysis for biological processes and signaling pathways indicated that the regulation of epithelial cell proliferation, positive regulation of cell cycle/cell proliferation/cell division and regulation of cell proliferation/cell division/cell growth were enriched in genes downregulated by BI 853520 treatment (Fig. 3A). In line with this finding, gene set enrichment analysis confirmed a significant reduction in the relative expression of genes important for cell cycle and positive regulation of mitotic cell cycle (including cyclin-dependent kinase 1 and 4; Cdk1: log2 fold-change= -0.4519, FDR= 4.24e-03; Cdk4: log2 fold-change= -0.3072, FDR= 0.003718), while the negative regulation of cell proliferation was increased following BI 853520 treatment (Fig. 3C; Suppl. Fig. 2C).
2019-07-19 | GSE116117 | GEO
Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
2020-08-20 | GSE128385 | GEO