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Synergistic activity of BET inhibitor BI 894999 with PLK inhibitor volasertib in AML in vitro and in vivo

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103068 | GEO | 2018/02/27

REPOSITORIES: GEO

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Homo sapiens

Project description:Synergistic activity of BET inhibitor BI 894999 with PLK inhibitor volasertib in AML in vitro and in vivo

| PRJNA400080 | ENA

The novel BETi BI 894999 represses super-enhancer associated transcription and synergizes with CDK9 inhibition in AML by induction of apoptosis

Project description:Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood. Mechanistic studies show that BI 894999 targets super-enhancer-regulated oncogenes and other lineage-specific factors, which are involved in the maintenance of the disease state. BI 894999 is active as monotherapy in AML xenografts, and in addition leads to strongly enhanced antitumor effects in combination with CDK9 inhibitors. This treatment combination results in a marked decrease of global p-Ser2 RNA polymerase II levels and leads to rapid induction of apoptosis in vitro and in vivo. Together, these data provide a strong rationale for the clinical evaluation of BI 894999 in AML.

2018-03-02 | GSE101821 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [scRNA-Seq]

Project description:Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

2024-02-01 | GSE252745 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [ATAC-Seq]

2024-02-01 | GSE252743 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [Stranded mRNA-Seq]

2024-02-01 | GSE252740 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [ChIP-Seq]

2024-02-01 | GSE252739 | GEO

Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic

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

Targeting protein tyrosine phosphatase non-receptor type 2 with a novel inhibitor for the treatment of acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.

2024-01-24 | PXD048854 | iProX

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

Project description:In this study we aimed to identify off-targets of polo-like kinase 1 (Plk1) small molecule inhibitor volasertib. Plk1 is an important cell cycle kinase and an attractive target for anticancer treatment. Volasertib is ATP-competitive small molecules that may also block the ATP-pocket of other proteins. Despite the fatal infections and negative survival in a phase III trial on volasertib in acute myeloid leukemia volasertib has been a promising treatment option in children with rhabdomyosarcoma. Therefore, there is a need to understand the nature of adverse effects that possibly originate from the off-target proteins. We used thermal proteome profiling (TPP) to identify proteins that have a change in the thermal stability after treatment with volasertib. The temperature of aggregation of several proteins involved in prostaglandin and phosphatidyl-inositol phosphate metabolism increased after treatment with volasertib. PIP4K2A and ZADH2 were stabilized both by treatment in living cells and cell lysate. Functional disruption of these proteins affects the immune response and fatty acid metabolism. In addition, volasertib was found to affect transcriptional coactivators, normal and alternative RNA splicing regulators and proteins involved in the intracellular transport regulation. Our data suggests that the identified proteins may contribute more to the understanding of anti-tumor effect of volasertib.

2021-08-23 | PXD024040 | Pride

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

2021-08-23 | PXD023757 | Pride

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