Quantitative analysis of bi-modal binding of BET proteins at promoters predicts I-BET sensitivity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA494237 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7947470.fastq.gz | Fastqsanger.gz | |||
| SRR7947480.fastq.gz | Fastqsanger.gz | |||
| SRR7947490.fastq.gz | Fastqsanger.gz | |||
| SRR7947500.fastq.gz | Fastqsanger.gz | |||
| SRR7947510.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.
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Project description:H3K4me1 distribution at promoters predicts the poised epigenetic state
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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.
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