Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA295418 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:assess the efficacy of OTX015 (MK-8628) BET inhibitor in vitro and in vivo triple negative breast cancer models
2017-01-03 | GSE79721 | GEO
Project description:Assess the efficacy of OTX015 (MK-8628) BET inhibitor, with respect to various lung carcinomas tumors, and to characterize its mechanism of action
2017-01-03 | GSE72961 | GEO
Project description:The BET Bromodomain Inhibitor OTX015/MK-8628 modulates microRNA expression in Diffuse Large B-Cell Lymphoma
| PRJNA387574 | ENA
Project description:Several studies demonstrate that the bromodomain inhibitor OTX015 has preclinical antitumor activity in a variety of solid tumors and hematologic cancers. However, translation of these data to molecules suitable for clinical development has not yet to be accomplished in multiple myeloma (MM). Here, we identified genes and biologic processes that underpin the antimyeloma activity of OTX015 with global transcriptomics. OTX015 exerted strong antiproliferative effect and induced cell cycle arrest in vitro. Gene expression profiling showed that OTX015 targeted NF-κB, EGFR, cell cycle regulation, cancer proliferation signaling pathway. Gene expression signatures associated with different sensitivity to OTX015 were also identified. The data also showed that oral administration of OTX015 displayed significant antitumor activity in mice model of disseminated human myeloma. In addition, our study provided the first evidence and rationale that OTX015 could promoted osteoblast differentiation of mesenchymal stem cells (MSCs) and inhibited osteoclast formation and resorption in vivo experiments. Herein we expanded the mechanistic understanding of BET inhibitors OTX015 in MM. Our preclinical studies provided a strong rationale for extending the clinical testing of the novel antimyeloma agent OTX015 and revealed insights into biologic pathways required for myeloma cell proliferation.
2019-03-08 | GSE111422 | GEO
Project description:Aberrant changes in microRNAs (miRNAs) contribute to lymphomagenesis and represent potential therapeutic targets. OTX015 (MK-8628), a bromodomain and extra-terminal domain (BET) inhibitor (BETi), has demonstrated preclinical and clinical activity in haematological tumours. To better understand the mechanism of action of OTX015 we studied its effects on miRNAs in lymphomas. We performed miRNA profiling of DLBCL cells treated with OTX015 and observed changes in the expression levels of a subset of miRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p, which are known to play a role in lymphomagenesis and/or resistance to chemotherapy. Analysis of publicly available BRD4 ChIP-Seq data of DLBCL cells treated with the BETi JQ1 showed that BRD4 was bound to the upstream regulatory regions of multiple miRNA genes and that this binding decreased following BETi. Alignment of our miRNA profiling data with the BRD4 ChIP-Seq data revealed that many miRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following BETi treatment, indicating that BRD4 directly modulated miRNA expression in lymphoma. Among the miRNAs upregulated in response to OTX015 was miR-96-5p, a miRNA known to play a role in B-cell transformation. In lymphomas, miR-96-5p transcription is repressed by the arginine methyltransferase PRMT5. In turn, PRMT5 translation is inhibited by miR-96-5p. We demonstrated that BRD4 bound to the 5’ regulatory region of PRMT5 and that following BET inhibition PRMT5 expression decreased, BRD4 binding to the 5’ region of PRMT5 was reduced and enrichment of PRMT5 at the miR-96-5p promoter lessened. Our results demonstrate that BRD4 binds to the promoters of miRNA genes to directly modulate their expression in lymphoma cells and that BETi administration results in decreased binding of BRD4 to the promoters of specific miRNAs to reduce their expression. Additionally, we show that BETi treatment can affect the expression of genes that control miRNA transcription to indirectly modulate miRNA expression. The data presented here indicate that the ability of BETi to inhibit or activate specific signalling pathways and processes critical to lymphoma cell proliferation and survival is in part due to changes in miRNA expression.
2018-11-21 | GSE99208 | GEO
Project description:The BET Bromodomain inhibitor OTX015 (MK-8628) in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance
| PRJNA432931 | ENA
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
2016-03-14 | E-GEOD-77042 | biostudies-arrayexpress
Project description:Transcriptional profiling of the human pancreatic cancer cell line SUIT-2 that were infected with a GFP encoding adenoviral construct based on Human Adenovirus 5 and treated with epigenetic modifiers I-bet-762, NEO27034 or OTX015 compared to uninfected and untreated cells. Cells were infected with 1pfu AdWTGFP in serum free media for 2 hours. Cells were then washed and cultured in media containing 2% FBS for 10 hours. Cells were then treated with I-bet-762, NEO27034, OTX015 or DMSO in media containing 2% FBS for 12 hours. Infected GFP+ cells were isolated by FACS. GFP+ and control cells were processed for RNA-seq.
2024-02-14 | E-MTAB-13108 | biostudies-arrayexpress
Project description:Activity of the BET Bromodomain inhibitor OTX015 (MK8628) in mantle cell lymphoma as single agent and in combination
2018-11-21 | GSE110134 | GEO
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity.
2016-03-14 | GSE77042 | GEO