Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic
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ABSTRACT:
PROVIDER: PRJNA759622 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15689100.fastq.gz | Fastqsanger.gz | |||
| SRR15689101.fastq.gz | Fastqsanger.gz | |||
| SRR15689102.fastq.gz | Fastqsanger.gz | |||
| SRR15689103.fastq.gz | Fastqsanger.gz | |||
| SRR15689104.fastq.gz | Fastqsanger.gz |
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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: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:Quantitative analysis of bi-modal binding of BET proteins at promoters predicts I-BET sensitivity
| PRJNA494237 | ENA
Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, FcγRII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/β-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/β-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies. Total RNA obtained from iBET resistant and sensitive cells
2015-09-15 | E-GEOD-63575 | biostudies-arrayexpress
Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers1,2. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, Fc³RII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/²-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/²-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies. Comparison of iBET resistant and sensitive cell lines
2015-09-15 | E-GEOD-63681 | biostudies-arrayexpress
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:Expression profiling PDE4B inhibitor BI 1015550 treatment in a therapeutic Rat Lung Bleomycin Model
| PRJNA1043126 | ENA
Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, FcγRII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/β-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/β-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies.
2015-09-15 | GSE63575 | 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:Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). Although several bet inhibitors have entered clinical trials, few are brain penetrant. We have generated UM-002, a novel brain penetrant BET inhibitor that reduces GBM cell proliferation in vitro and in a human cerebral brain organoid model. Since UM-002 is more potent than other BET inhibitors, it could potentially be developed for GBM treatment. Furthermore, UM-002 treatment reduces the expression of cell-cycle related genes in vivo, and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNAsequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. Importantly, they also provide an integrated dataset that combines in vitro and ex vivo studies with in vivo single-cell RNA-sequencing to characterize a novel BET inhibitor in GBM.
2021-12-01 | GSE173146 | GEO