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Journal articles on the topic "OTX015"
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Bonetti, Paola, Michela Boi, Maurilio Ponzoni, Maria Grazia Tibiletti, Anastasios Stahis, Giorgio Inghirami, Kay Noel, Emanuele Zucca, and Francesco Bertoni. "The Brd-Inhibitor OTX015 Is Active in Pre-Clinical Models of Mature B-Cell Lymphoid Tumors." Blood 120, no. 21 (November 16, 2012): 1657. http://dx.doi.org/10.1182/blood.v120.21.1657.1657.
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Abstract Abstract 1657 Background: Bromodomain-containing proteins play an important role in gene expression regulation, via chromatin structure remodelling. Antitumor activity has been reported in acute and chronic hematological malignancies using inhibitors of BRD2/3/4, members of the Bromodomain and Extraterminal (BET) family. Here, we report anti-proliferative activity of OTX015, a novel selective orally bioavailable BRD2/3/4 inhibitor, in a large panel of cell lines derived from mature B-cell lymphoid tumors. Material and Methods: Established human cell lines derived from 13 diffuse large B-cell lymphoma (DLBCL), 4 mantle cell lymphoma (MCL), three splenic marginal zone lymphoma (SMZL) and from three multiple myeloma (MM) were treated with increasing doses of OTX015 (OncoEthix SA) and MTT assays were performed after 72 hours exposure. For cell cycle analysis, cells were treated and stained with Click-iT Edu Flow Cytometry Assay Kits (Invitrogen) and 7-AAD and analyzed for DNA content using a FACScan flow cytometer. Results were analyzed with FlowJo 7.6.3 software. RNA extracted using the Qiagen RNAEasy kit and reverse-transcribed using the Superscript First-Strand Synthesis System for RT-PCR kit according to the manufacturer's instructions. RT-PCR was performed using Fast SYBR Green Master Mix on a StepOnePlus Real-Time PCR System. For senescence detection, cells were stained using a b-Galactosidase Staining Kit (Calbiochem). Results: OTX015 demonstrated anti-proliferative activity in DLBCL cell lines (median IC50 0.192μM; range 0.069–12.68μM). Similar results were obtained on SMZL (median IC50 0.165μM, range 0.105–0.24μM), and on MM cell lines (median IC50 0.449μM; range 0.06–0.7μM). Conversely, MCL cell lines appeared less sensitive to OTX015 (median IC50 2.01μM; range 1.22- >15μM). Among DLBCL cell lines, there was no significant difference based upon the cell of origin of the cell lines. OTX105 caused a cell cycle arrest in G1 in a dose-dependent manner in 5/5 DLBCL and 3/3 MM cell lines, without an increase in cell death. An increase in the percentage of senescent cells after treatment with the BRD-inhibitor was observed in 1/1 sensitive DLBCL cell line. In order to understand the mechanism of action of OTX015, we assessed MYC mRNA levels before and after 24h treatment with increasing doses. We observed a dose-dependent suppression of MYC mRNA by OTX015 in 4/5 DLBCL and in 2/2 MM cell lines. In DLBCL, down-regulation of MYC mRNA was observed within 1h after treatment with OTX015, suggesting a direct effect of the compound on the MYC gene. To determine whether the suppression of MYC gene by OTX015 was reversible, DLBCL cell lines were treated for 2h with OTX015 and then the inhibitor was removed from the media. MYC mRNA suppression appeared reversible, as shown in DLBCL cell lines, which, after 2h exposure to OTX015, showed a time-dependent restoration of MYC mRNA expression to untreated levels after 2–3h. In one of the most sensitive DLBCL cell lines no MYC mRNA down-regulation was observed after treatment, suggesting that alternative pathways can be affected by BRD-inhibition. Conclusion: OTX015 is a new potent BRD-inhibitor with evident anti-proliferative activity in several cell lines representative of mature B-cell tumors. An apparently reversible down-regulation of MYC mRNA was commonly observed, appearing as a possible mechanism of action of the compound. The compound appears worth of further investigation as a new promising therapeutic agent in mature B-cell origin malignancies. A phase I trial is scheduled to start in 2012. Disclosures: Bonetti: OncoEthix SA: Research Funding. Inghirami:OncoEthix SA: Research Funding. Noel:OncoEthix SA: Membership on an entity's Board of Directors or advisory committees. Bertoni:OncoEthix SA: Research Funding.
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Coudé, Marie-Magdelaine, Thorsten Braun, Jeannig Berrou, Mélanie Dupont, Raphael Itzykson, Aline Masse, Emmanuel Raffoux, et al. "Bromodomain Inhibition By OTX015 Regulates c-MYC and HEXIM1 in a Panel of Human Acute Leukemia Cell Lines." Blood 124, no. 21 (December 6, 2014): 5957. http://dx.doi.org/10.1182/blood.v124.21.5957.5957.
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Abstract Background: The bromodomain-containing protein 4 (BRD4) activates the transcription elongation factor b (P-TEFb) which regulates RNA polymerase II. Conversely, hexamethylene bisacetamide (HMBA) inducible protein 1 (HEXIM1) inactivates P-TEFb. BRD4/HEXIM1 interplay influences cell cycle progression and tumorigenesis. It has been widely demonstrated that BRD4 knockdown or inhibition by JQ1 is associated with c-MYC downregulation and antileukemic activity. We recently reported that the small molecule BRD2/3/4 inhibitor OTX015 (Oncoethix, Lausanne, Switzerland), currently in clinical development, mimics the effects of JQ1 (Braun et al, ASH 2013). We evaluated the effect of OTX015 on c-MYC, BRD2/3/4, and HEXIM1 in human in vitro leukemic models. Methods: c-MYC, BRD2/3/4 and HEXIM1 expression was assessed in six acute myeloid leukemia (AML; K562, HL-60, NB4, NOMO-1, KG1, OCI-AML3) and two acute lymphoid leukemia (ALL; JURKAT and RS4-11) cell lines after exposure to 500 nM OTX015. Quantitative RT-PCR and Western blotting were performed at different time points (24-72h). A heatmap was computed with R-software. Results: c-MYC RNA levels were ubiquitously downregulated in all AML and ALL cell lines after 24h exposure to OTX015 (Figure 1). c-MYC protein levels decreased to a variable extent at 24-72h in all cell lines evaluated other than KG1. BRD2, BRD3 and BRD4 mRNA expression was significantly decreased in K562 cells (known to be OTX015-resistant) after 48h exposure to OTX015 but was increased in HL60 and NOMO-1 cells, while minimal to no increases were observed in other cell lines. OTX015 induced a decrease in BRD2 protein expression in most cell lines, but not in K562 cells. In contrast, decreased BRD4 protein expression was only seen in the OCI-AML3, NB4 and K562 cell lines. BRD3 protein levels were not modified after OTX015 exposure in all cell lines evaluated other than KG1. HEXIM1 mRNA expression increased after 24h exposure to 500 nM OTX015 in all cell lines except OTX015-resistant K562 cells in which the increase was considered insignificant (less than two-fold). Increases in HEXIM1 protein levels were observed in OCI-AML3, JURKAT and RS4-11 cell lines at 24-72h but not in K562 cells. Conclusion: Taken together, these results show that BRD inhibition by OTX015 modulates HEXIM1 gene and protein expression, in addition to c-MYC decrease and BRD variations. HEXIM1 upregulation seems to be restricted to OTX015-sensitive cell lines and was not significantly affected in OTX015-resistant K562 cells. Further studies are needed to clarify the role of HEXIM1 in antileukemic activity of BRD inhibitors. Figure 1: Heatmap of gene expression after exposure to 500 nM OTX015 for 24 or 48h in AML and ALL cell lines. Repression in blue. Overexpression in red. Figure 1:. Heatmap of gene expression after exposure to 500 nM OTX015 for 24 or 48h in AML and ALL cell lines. Repression in blue. Overexpression in red. Disclosures Riveiro: OTD: Employment. Herait:OncoEthix: Employment. Dombret:OncoEthix: Research Funding.
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Roulin, Louise, Ashfaq Ali, Aline Masse, Marie-Magdelaine Coudé, Dominique Bluteau, Thorsten Braun, Jeannig Berrou, et al. "Activity of OTX015 (MK-8628), a BET-Bromodomain Inhibitor, in Acute Myeloid Leukemia (AML) Progenitor Cells." Blood 126, no. 23 (December 3, 2015): 2588. http://dx.doi.org/10.1182/blood.v126.23.2588.2588.
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Abstract CONTEXT: Eradication of leukemic progenitor cells, defined by functional assays such as long-term culture (leukemic long-term culture initiating cells [L-LTC-IC]) is the goal of therapy in AML. Bromodomain and ExtraTerminal (BET) proteins are epigenetic readers that regulate the expression of genes with super-enhancers, including CMYC. BET inhibitors (BETi) such as JQ1 induce proliferation arrest and apoptosis in murine models of AML, in human AML cell lines and primary blasts. Their activity in human leukemic progenitors has not yet been reported. OTX015 (MK-8626) is an orally available BETi that can be safely administered to patients with a continuous low-dose regimen (Dombret et al. Blood. 2014). Single-dose exposure to OTX015 induces gene expression modulation characteristic of bromodomain inhibition, including downregulation of CMYC and upregulation of HEXIM1, inhibiting the viability of AML cell lines, and inducing apoptosis in primary AML blasts (Coudé et al. Oncotarget. 2015). To address the activity of OTX015 on leukemic progenitors, we analyzed (A) the clonogenicity of AML cell lines and (B) the frequency of primary L-LTC-IC after repeated low-dose exposure to OTX015. METHODS: (A) Five AML cell lines (OTX015 IC50 60 - 10,000 nM) were studied: OCI-AML3, NOMO-1, HL-60, KG1a and K562. After 24h starvation, OTX015 or vehicle (DMSO) was added daily to the culture medium for 3 days at various concentrations. After 96h, cells were assessed for gene expression by RT-qPCR and seeded in methycellulose. Colonies were scored after 14 days. (B) Bone-marrow mononuclear cells (BMNC) from AML patients obtained at diagnosis after informed consent were cultured for three weeks in a niche-like hypoxic milieu shown to maintain leukemic stem cells (Griessinger et al. Stem Cells Transl Med. 2014). OTX015 200 nM or DMSO was added weekly. This concentration is in the range of trough concentrations achievable at the MTD of OTX015 in phase I trials. Residual leukemic cells were sorted and plated on methylcellulose. Colonies were scored after 14 days. The resulting L-LTC-IC frequency was reported relative to the number of BMNC initially seeded. RESULTS: (A) To dissect the effect of OTX015 on AML progenitors from that on the leukemic bulk, we determined for each cell line a maximal OTX015 concentration that could be administered repeatedly for 3 days without significantly impairing proliferation or viability (MTT) at day 4 of culture (referred as low-dose concentration). As expected, this target concentration, ranging from 50 to 500 nM, was lower in cell lines with low OTX015 IC50. This prolonged low-dose exposure to OTX015 recapitulated BETi-associated gene expression changes including CMYC downregulation and HEXIM1 upregulation in all cell lines, and significantly reduced clonogenicity compared to DMSO in 4/5 cell lines, but not in NPM1-mutated OCI-AML3 cells (IC50: 60 nM, target concentration 50 nM), despite modulation of CMYC and HEXIM1 expression. Overall, there was no correlation between the level of CMYC repression and clonogenicity. Transcriptome analyses are ongoing to identify gene expression changes specifically associated with inhibition of clonogenicity. (B) L-LTC-IC frequency after prolonged exposure to 200 nM OTX015 was determined in specimens from 11 AML patients with variable oncogenetics. L-LTC-IC frequency was reduced in 5/11 patients, reaching statistical significance in 3 cases; OTX015 reduced L-L-LTC-IC in 3 of 4 NPM1-mutated samples, but not in any of the 3 patients with high-risk cytogenetics. No clear correlation was found between induction of apoptosis on primary blasts after short-term, and L-LTC-IC reduction after long-term 200nM OTX015 exposure respectively. Patients' samples number is being extended to identify oncogenetic predictors of L-LTC-IC reduction. CONCLUSION: Our results suggest that in AML cell lines or primary samples, prolonged exposure to low concentrations of the clinically-available BET inhibitor OTX015 results in activity against leukemic progenitors independent of induction of proliferation arrest or apoptosis in blasts. Molecular mechanisms and oncogenic markers of this activity are being investigated. These results warrant clinical investigation of the anti-leukemic properties of prolonged low-dose OTX015 administration. Disclosures Riveiro: Oncoethix: Research Funding; OTD: Employment. Herait:Oncoethix: Other: shareholder; Oncoethix: Other: Chief medical officer; Oncoethix: Other: shareholder. Dombret:Oncoethix: Research Funding. Itzykson:Oncoethix: Research Funding.
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Bernasconi, Elena, Chiara Tarantelli, Eugenio Gaudio, Ivo Kwee, Andrea Rinaldi, Luciano Cascione, Anastasios Stathis, Maria Eugenia Riveiro, Emanuele Zucca, and Francesco Bertoni. "The BET-Bromodomain Inhibitor OTX015 Is Active As a Single Agent and in Combination with Other Targeted Drugs in Preclinical Models of Mantle Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 3113. http://dx.doi.org/10.1182/blood.v124.21.3113.3113.
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Abstract Background. Mantle cell lymphoma (MCL), which is characterized by the deregulation of cyclin D1 (CCND1), is one of the most common lymphoma subtypes, accounting for 5-10% of all cases. MCL prognosis is often very poor. Several novel non-chemotherapeutic agents have shown promising activity in MCL, but novel agents and in particular new drug combinations are needed to improve patients' outcome. Aberrant changes in histone modifications, DNA methylation and expression levels of non-coding RNA contribute to MCL pathogenesis and represent potential therapeutic targets. Bromodomain and extra-terminal (BET) proteins are epigenetic readers contributing to gene transcription. OTX015 is a bromodomain (BRD) inhibitor that has shown preclinical activity in hematologic and solid tumor models (Gaudio et al, AACR 2014; Noel et al, EORTC-NCI-AACR 2013) as well as promising early results in an ongoing phase I study (Herait et al, AACR 2014; NCT01713582). Here, we present preclinical evidence of OTX015 activity in combination with other targeted drugs in MCL. Material and methods. MCL cell lines (REC1, MAVER1, UPN1, JeKo1, SP53, Mino, Granta519) were exposed to increasing doses of OTX015 alone or in combination with increasing doses of other drugs, including everolimus, BEZ235, ibrutinib, carfilzomib, pomalidomide, 5-AZA, vorinostat and dexamethasone. The MTT assay was performed after 72h exposure. Real-time PCR and Western blotting were used for RNA and protein expression analyses. Synergy was assessed by the Chou-Talalay combination index (CI) with the Synergy R package: CI<0.3, strong synergy; 0.3-0.9, synergy; 0.9-1.1, additive effect. Results. OTX015 showed antiproliferative activity as a single agent in 6/7 MCL cell lines with IC50s < 500 nM. Four MCL cell lines were exposed to DMSO or OTX015 (500 nM and IC50) for 4 and 24h to evaluate expression of CCND1 and other members of signaling pathways known to be impacted by BRD inhibitors. No reduction in CCND1 was observed at the RNA or protein levels after OTX015 exposure. However, MYC was downregulated and the transcriptional regulator HEXIM1 and histone-coding genes were upregulated. In light of reported strong synergy between OTX015 and the mTOR inhibitor everolimus in diffuse large B-cell lymphoma, we evaluated OTX015 combined with everolimus or the dual PI3K/mTOR inhibitor BEZ235 in 6 MCL cell lines (REC1, MAVER1, UPN1, JeKo1, SP53, Mino). In addition, combinations of OTX015 with the BTK-inhibitor ibrutinib, the proteasome inhibitor carfilzomib, the immunomodulator pomalidomide, the demethylating agent 5-AZA, the HDAC-inhibitor vorinostat, and the glucocorticoid dexamethasone were assessed in REC1 and MAVER1. Combinations of OTX015 with everolimus, pomalidomide, dexamethasone, and ibrutinib showed the strongest activity (Fig 1). Strong synergy between BEZ235 and OTX015 was only seen in the ibrutinib-resistant cell line MAVER1. Conclusions. OTX015 showed preclinical activity as a single agent in MCL cells. The mechanism of action does not appear to involve CCDN1 down-regulation and gene expression profiling studies will be needed to identify the involved pathways. OTX015 had additive or synergistic activity with several targeted compounds in multiple MCL cell lines, identifying combinations that may merit further investigation in the preclinical and clinical settings. Fig. 1. Chou-Talalay analysis of OTX015 combinations in MCL cell lines. Y-axis: CI<0.3, strong synergy; 0.3-0.9, synergy; 0.9-1.1, additive effect; > 2.25, antagonism. Outliers were excluded. C.I., Combination Index. Fig. 1. Chou-Talalay analysis of OTX015 combinations in MCL cell lines. Y-axis: CI<0.3, strong synergy; 0.3-0.9, synergy; 0.9-1.1, additive effect; > 2.25, antagonism. Outliers were excluded. C.I., Combination Index. Disclosures Stathis: Oncoethix SA: Consultancy, Research Funding. Riveiro:Oncoethix SA: Consultancy, Research Funding; Oncology Therapeutic Development: Employment. Bertoni:Oncoethix SA: Research Funding.
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Riveiro, Maria Eugenia, Lucile Astorgues-Xerri, Charlotte Canet-jourdan, Mohamed Bekradda, Esteban Cvitkovic, Patrice Herait, and Eric Raymond. "Preclinical Evaluation of the BET-Bromodomain (BET-BRD) Inhibitor OTX015 in Leukemia Cell Lines Harboring the JAK2 V617F Mutation." Blood 124, no. 21 (December 6, 2014): 873. http://dx.doi.org/10.1182/blood.v124.21.873.873.
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Abstract Background: Exposure of cancer cells to BET-BRD protein inhibitors has been associated with a significant downregulation of C-MYC expression, leading to suppression of the transcriptional program linked to proliferation and survival. C-MYC mRNA expression, mediated by STAT5 activation, is induced by the JAK2 (V617F) mutation (JAK2mu) in transfected BA/F3 cells (Funakoshi-Tago, et al. 2013). We selected JAK2mu leukemia-derived cell lines for preclinical evaluation of OTX015 (Oncoethix, Switzerland), a selective orally-bioavailable inhibitor of BET-BRD proteins with promising early results in an ongoing phase I study in hematologic malignancies (Herait et al, AACR 2014, NCT01713582). Material and Methods: Antiproliferative effects of OTX015 and JQ1 were evaluated in three established JAK2mu human myeloid leukemia cell lines (SET2, MUTZ8, HEL 92.1.7). GI50 (OTX015 concentration inducing 50% growth inhibition) and Emax (% cell proliferation at 6 µM OTX015) values were determined by MTT assay after 72h exposure. Protein levels were analyzed by Western blot, and RT-PCR was performed with Fast SYBR Green Master Mix on a StepOnePlus Real-Time PCR System. For cell cycle analysis, cells were stained with propidium iodide and analyzed with a FACScan flow cytometer. Induction of apoptosis was evaluated by Annexin-V. Simultaneous schedules of OTX015 combined with ruxolitinib, a JAK2 inhibitor, were evaluated. Combination index (CI) was determined using the Chou & Talalay method; CI<1 reflects synergy, CI=1 additivity and CI>1 antagonism. Results: After 72h exposure, SET2 was the most sensitive cell line (GI50=0.12 µM and Emax=15%), and HEL92.1.7 cells had a GI50=1.9 µM with an Emax=23%. MUTZ8 was the most resistant cell line with an Emax=61%. Similar GI50 and Emax values are observed with JQ1. A significant increase in the fraction of apoptotic cells was observed in SET2 cells after 72h 500 nM OTX015 exposure. Non-significant increases in Annexin-positive cells were seen in HEL92.1.7 and MUTZ8 cells. Cell cycle analysis revealed a significant increase in the percentage of SET2 cells in subG0/G1 after 24, 48, and 72h 500 nM OTX015, correlating with the increase in apoptosis. Conversely, an increase in the percent cells in the G1 phase was observed in HEL 92.1.7 cells. After 4h 500 nM OTX015, BRD2 mRNA levels were significantly increased in all three cell lines, whereas BRD3 levels were not modified. BRD4 mRNA levels increased significantly after 48h in SET2 cells. OTX015 treatment induced a transitory reduction of C-MYC mRNA levels after 4h with an increase at 24h in all cell lines. At the protein level, C-MYC decreased substantially in SET2 cells after 4h, with complete disappearance after 48h without recovery, while in the less sensitive MUTZ8 cell line, the decrease in C-MYC protein levels was transitory. Conversely, this proto-oncogene was not modified in HEL92.1.7 cells. In addition, p-STAT5 protein was downregulated by OTX015 in SET2 cells, but was increased in MUTZ8 cells after longer exposure time. Furthermore, BCL2 mRNA and protein levels decreased in SET2 cells, correlating with the apoptosis induction seen with OTX015 treatment. In HEL92.1.7 cells, P21 mRNA levels and cyclin D1 protein levels increased after 4h and 48h OTX015 treatment, respectively. Moreover, concomitant combination of OTX015 with ruxolitinib showed a highly antagonist effect (CI>7) in SET2 cells, the most sensitive cell line to both agents. On the other hand, very strong synergy was observed in HEL92.1.7 (CI=0.19) and MUTZ8 (CI=0.41), despite their low sensitivity to single agent OTX015. Conclusions. Our findings demonstrate that OTX015 exhibits potent activity against cultured leukemic cells expressing the JAK2 V617F mutation, inducing apoptosis or cell cycle arrest at submicromolar concentrations. This activity correlates with modulation of C-MYC, p-STAT5, BCL2, P21 and cyclin D1 mRNA and protein levels following OTX015 treatment. Our study highlights the novel and synergistic activity of the combination of a BRD antagonist and a JAK inhibitor in human leukemic cells harboring the JAK2 V617 F mutation, supporting the rationale for in vivo testing of OTX015 in combination with JAK inhibitors in leukemic JAK2mu models. Disclosures Riveiro: Oncoethix SA: Research Funding. Astorgues-Xerri:Oncoethix SA: Research Funding. Canet-jourdan:Oncoethix SA: Research Funding. Bekradda:Oncoethix SA: Research Funding. Cvitkovic:Oncoethix SA: Membership on an entity's Board of Directors or advisory committees, Shareholder and CSO Other. Herait:Oncoethix SA: CMO and Shareholder Other. Raymond:Oncoethix SA: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Gaudio, Eugenio, Ivo Kwee, Andrea Rinaldi, Michela Boi, Elena Bernasconi, Monica Testoni, Anastasios Stathis, et al. "Genetic Factors Predicting The Response To BET Bromodomain Inhibitors In Lymphoma Lead To New Synergistic Combinations." Blood 122, no. 21 (November 15, 2013): 3070. http://dx.doi.org/10.1182/blood.v122.21.3070.3070.
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Abstract Epigenome deregulation in cancer cells affects transcription of oncogenes and tumor suppressor genes. BET Bromodomain proteins recognize chromatin modifications and act as epigenetic readers contributing to gene transcription. BET Bromodomain inhibitors showed promising pre-clinical activity in hematological and solid tumors and are currently in phase I studies. The mechanism of action and relevant affected genes are not fully characterized and there are no established response predictors. We have shown activity of BET Bromodomain OTX015 in lymphoma cell lines (ASH 2012; ICML 2013). This study aimed at elucidating pathways and genes affecting response/resistance to BET Bromodomain inhibitors in lymphomas. Methods Baseline gene expression profiles (GEP) were obtained in 38 cell lines [22 diffuse large B-cell lymphoma (DLBCL), 8 anaplastic large T-cell lymphoma, 4 mantle cell lymphoma, 3 splenic marginal zone lymphoma, 1 chronic lymphocytic leukemia] with Illumina HumanHT-12 v4 Expression BeadChip. Genetic and biologic information were collected from literature. GEP/IC50 correlation (ASH 2012; ICML 2013) was assessed by Pearson correlation. Associations in two-way tables were tested for statistical significance using either chi-square or Fisher exact test, as appropriate. Differential expression analysis was performed using LIMMA, followed by multiple test correction using the BH method. Enrichment of functionally-related genes was evaluated by GSEA. For combination studies, 3 germinal center B-cell (GCB) and 2 activated B-cell (ABC) DLBCL were exposed to increasing doses of OTX015 alone or in combination with increasing doses of targeted agents for 72 hours, followed by MTT assay. Synergy was assessed by Chou-Talalay combination index (CI) with Synergy R package. Results Transcripts associated with resistance to OTX015 were significantly enriched of genes involved in cell cycle regulation, DNA repair, chromatin structure, early B-cell development, E2F/E2F2 target genes, IL6-dependent genes, and mRNA processing. Conversely, transcripts associated with OTX015 sensitivity were enriched of hypoxia-regulated genes, interferon target genes, STAT3 targets, and involved in glucose metabolism. Genes associated with OTX015 sensitivity included LDHA, PGK1 (glucose metabolism) and VEGFA (hypoxia), while BCL2L1/BCLXL, BIRC5/survivin (anti-apoptosis), ERCC1 (DNA repair), TAF1A and BRD7 (transcription regulation) were correlated with reduced sensitivity. GEP identified 50 transcripts differentially expressed, including IL6, HCK, SGK1, MARCH1 and TRAFD1, between cells undergoing or not apoptosis after OTX015 exposure. GSEA showed significant enrichment of genes involved in IL-10 signaling pathway. While there was no association between response to OTX015<500nM and presence of translocated MYC, analysis of genetic and biologic features identified the ABC phenotype (P=.008) and presence of concomitant somatic mutations in MYD88 and CD79B or CARD11 genes and wild type TP53 (P=.027) as associated with apoptosis. Based on these observations and since mutated MYD88 interacts with BTK and MYD88/CD79B mutations have been associated with clinical responses with the BTK inhibitor ibrutinib, we evaluated OTX015 combination with this compound. Synergy was observed in particular in ABC-DLBCL with a median CI of .04 (range .02-.1). The demonstrated down-regulation of the MYD88/JAK/STAT pathway after OTX015 treatment, as shown by additional GEP, highlighted the importance of this pathway for OTX015 activity. Other targeted agents (everolimus, lenalidomide, rituximab, decitabine, vorinostat) appeared to synergize with OTX015 (Fig 1). The mTOR inhibitor everolimus presented a very strong synergism with a median CI of .11 (.1-.2), in accordance with the association between OTX015 sensitivity to high glucose metabolism and high levels of SGK1 in cells undergoing apoptosis. Conclusions Our study identified genetic mechanisms contributing to the response to BET Bromodomain inhibitors and promising combination schemes, such as OTX015/everolimus, to be further investigated. Disclosures: Stathis: Oncoethix: NCT01713582 PI Other. Herait:Oncoethix: Membership on an entity’s Board of Directors or advisory committees. Noel:Oncoethix: Membership on an entity’s Board of Directors or advisory committees. Inghirami:Oncoethix: Research Funding. Bertoni:Oncoethix: Research Funding.
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Megiorni, Francesca, Simona Camero, Paola Pontecorvi, Lucrezia Camicia, Francesco Marampon, Simona Ceccarelli, Eleni Anastasiadou, et al. "OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence." Cancers 13, no. 7 (March 25, 2021): 1519. http://dx.doi.org/10.3390/cancers13071519.
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Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC.
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Cascione, Luciano, Eugenio Gaudio, Elena Bernasconi, Chiara Tarantelli, Andrea Rinaldi, Monica Testoni, Riccardo Bomben, et al. "BET Bromodomain Inhibitor OTX015 Affects the Expression of Micrornas Involved in the Pathogenesis of Diffuse Large B-Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 4495. http://dx.doi.org/10.1182/blood.v124.21.4495.4495.
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Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, accounting for 30%-40% of all cases. Despite a major improvement in the cure rate, a large number of DLBCL patients lack therapeutic options. Aberrant changes in histone modifications, DNA methylation and expression levels of non-coding RNA, including microRNA (miRNA), contribute to DLBCL pathogenesis and represent potential therapeutic targets. OTX015 targets bromodomain and extra-terminal (BET) proteins, which are epigenetic readers contributing to gene transcription. It has shown preclinical activity in hematologic and solid tumor models (Gaudio et al, AACR 2014; Noel et al, EORTC-NCI-AACR 2013) and promising early results in an ongoing phase I study (Herait et al, AACR 2014; NCT01713582). To better understand the mechanism of action of OTX015, we studied molecular changes induced by this compound in DLBCL cell lines. Methods. Total RNA was extracted from 2 DLBCL cell lines, the germinal center B-cell (GCB) type DOHH2 and activated B-cell-like (ABC)-type SU-DHL-2, following treatment with 500 nM OTX015 or DMSO for 4h or 8h. RNA samples were labeled with cyanine-3 dye using the Agilent microRNA Complete Labeling System & Hyb Kit and hybridized to the Agilent Human microRNA microarray v.3. Raw expression values were obtained with Agilent Feature Extraction Software, log-transformed and normalized by the quantile method. Data were filtered to exclude relatively invariant features and those below the detection threshold. Limma (Linear Models for Microarray data analysis) was employed using R/Bioconductor and the filtered dataset. Baseline miRNA profiling was obtained from 22 DLBCL cell lines with the Nanostring nCounter Human v2 miRNA Expression Assay kit. Baseline gene expression profiling (GEP) was obtained in these cell lines with the Illumina HumanHT-12 v4 Expression BeadChip. Selected miRNA changes were validated by real-time PCR. Validated miRNA targets were retrieved using the miRWalk database (Dweep et al, 2011). Gene Set Enrichment Analysis (GSEA) software was used to assess enrichment of miRNA targets in the GEP datasets. Results. miRNA profiling of the GCB and ABC DLBCL cell lines exposed to OTX015 identified four downregulated miRNAs and eight which were upregulated. Among them, the oncomirs miR-92a-1-5p (log2 FC, -2.01; P=0.004) and miR-21-3p (log2 FC, -0.37; P=0.0045) were downregulated, while the tumor suppressor miR-96-5p (log2 FC, 0.39; P=0.041) was upregulated. Interestingly, changes of these miRNAs matched GEP variations of validated target genes (e.g., miR-92a-1-5p: CDKN1A, log2 FC, 0.81, CDKN2A, log2 FC, 0.81; miR-96-5p: MYC, log2 FC, -0.57, MYD88, log2 FC, -0.35). We then evaluated if these three miRNAs play a role in OTX015-sensitivity by obtaining baseline miRNA and GEP profiling data in 22 DLBCL cell lines. Compared to 8 cell lines with lower sensitivity to OTX015 (IC50 >500 nM), the 14 sensitive cell lines (IC50 <500 nM) presented lower miR-96-5p expression levels (log ratio, 2.12; P=0.026) and their GEPs were significantly enriched for validated miR-96-5p targets (normalized enrichment score, 1.4; P=0.026), suggesting miR-96-5p levels may predict response to OTX015. Conclusions. Changes in the expression levels of biologically relevant miRNAs may contribute to response to OTX015. miR-92a-1-5p, the oncomir which was most strongly downregulated by OTX015, is a member of the MYC target MIR17HG (mir-17-92 cluster), involved in the pathogenesis and chemo-resistance of lymphomas, mainly contributing to PI3K/AKT/mTOR pathway activation. Since the cell cycle transcriptional regulator E2F1 is targeted by mir-17-92, OTX015 may contribute to cell cycle arrest and to downregulation of the E2F1 target gene reported with BRD inhibitors in DLBCL cell lines. miR-21-3p, also downregulated by OTX015, is a well-known oncomir, and forced miR-21-3p expression in transgenic mice results in the development of leukemias and lymphomas. miR-96-5p, upregulated by OTX015, targets oncogenes such as RAS or MYC, and low expression has been reported in mantle cell lymphoma. Interestingly, low miR-96-5p baseline levels were associated with higher sensitivity to OTX015, an observation meriting validation in other tumor models and evaluation in clinical studies. Disclosures Stathis: Oncoethix SA: Consultancy, Research Funding. Riveiro:Oncoethix SA: Consultancy, Research Funding; Oncology Therapeutic Development: Employment. Bertoni:Oncoethix SA: Research Funding.
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Gaudio, Eugenio, Luciano Cascione, Maurilio Ponzoni, Chiara Tarantelli, Elena Bernasconi, Maria Eugenia Riveiro, Esteban Cvitkovic, Emanuele Zucca, and Francesco Bertoni. "The BET Inhibitor OTX015 (MK-8628) Shows in Vivo Antitumor Activity in Combination with Additional Targeted Agents in Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 126, no. 23 (December 3, 2015): 5119. http://dx.doi.org/10.1182/blood.v126.23.5119.5119.
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Abstract OTX015 (MK-8628) has shown anti-lymphoma activity in both the preclinical and clinical settings (Boi et al, CCR 2015; Stathis et al, EORT-NCI-AACR 2014). Here we report in vivo data on OTX015 in combination with four targeted compounds in DLBCL. Methods. NOD-Scid (NOD.CB17-Prkdcscid/NCrHsd) mice were subcutaneously engrafted with the activated B-cell like DLBCL cell line SUDHL2 (15 x106 cells) and then divided into 10 groups (6 mice each). Treatment with OTX015 was started 3 days after the graft, and treatments with other drugs were initiated when mice developed palpable tumors (100 mm3). Tumor size was measured two times per week using digital calipers. Tumor volumes were calculated using the equation V = [length x width2]/2 (width and length are the shortest and the longest diameters of each tumor, respectively). Tumor specimens were collected at the end of treatment and necrosis was semi-quantitatively defined on the total amount of neoplastic tissue. Results. Xenografts of SU-DHL-2 were treated with control or OTX015 (50 mg/kg once daily; QDx7/w x5w), the BTK-inhibitor ibrutinib (5 mg/kg; QDx2/w x5w), the mTOR-inhibitor everolimus (1 mg/kg, Qdx2/w x5w), the HDAC-inhibitor vorinostat (15 mg/kg; QDx2/w x5w), the anti-CD20 monoclonal antibody rituximab (3 mg/kg; QDx1/w x5w) as single agents or in OTX015-containing combinations. No weight loss was reported. OTX015, in accordance previously published data (Boi et al, CCR 2015), as single agent delayed tumor growth. Almost complete eradication of tumors was observed in mice treated with OTX015 combinations (p<0.001) (Figure 1). Three tumors for each group were H&E stained and necrosis percentage evaluated. Only control and vorinostat-treated tumors showed no or minimal (<5%) necrosis, which appeared higher in tumors treated with all the other drugs as single agents and in the combinations. Conclusions. OTX015-containing combinations with everolimus, ibrutinib, vorinostat and rituximab showed very promising in vivo activity in an ABC-DLBCL model, providing the rationale for future clinical studies. Figure 1. In vivo treatment of ABC-DLBCL SU-DHL-2 xenografts with MK-8228 as single agent and in combination with other targeted drugs. Figure 1. In vivo treatment of ABC-DLBCL SU-DHL-2 xenografts with MK-8228 as single agent and in combination with other targeted drugs. Disclosures Riveiro: Oncology Therapeutic Development: Employment. Cvitkovic:Oncology Therapeutic Development: Employment, Membership on an entity's Board of Directors or advisory committees. Bertoni:PIQUR Therapeutics AG: Research Funding; Oncology Therapeutic Development: Research Funding.
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Braun, Thorsten, marie Magdelaine Coude, Jeannig Berrou, Sibyl Bertrand, Eugenia Riveiro, Patrice Herait, Andre Baruchel, Hervé Dombret, and Claude Gardin. "Preclinical Study Of The Bromodomain Inhibitor OTX015 In Acute Myeloid (AML) and Lymphoid (ALL) Leukemias." Blood 122, no. 21 (November 15, 2013): 4218. http://dx.doi.org/10.1182/blood.v122.21.4218.4218.
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Abstract Background Bromodomain and extra-terminal (BET) proteins, including the ubiquitous BRD2/3/4 proteins, are epigenetic readers implicated in c-MYC transcription, cellular proliferation, cell-cycle progression, RNA elongation and DNA damage response. Using shRNA screening and BRD inhibitors, BRD4 has been established as a promising therapeutic target in acute leukemia (Zuber, Nature 2011). In the present study, we investigated the in vitro anti-leukemic effects of the small-molecule BRD2/3/4 inhibitor OTX015 (Oncoethix, Lausanne, Switzerland). Methods Expression of BRD2/3/4 and c-MYC was assessed by RQ-PCR in 5 myeloid (HL60, KG1, KG1a, K562, NOMO1) and 4 lymphoid (Jurkat, RS4-11, BV173, TOM1) leukemia cell lines and by Western blotting (WB) using commercial antibodies in the HL60, K562, Jurkat and RS4-11 lines. Nineteen AML and ten ALL patient banked leukemic cells were assayed by RQ-PCR only. Cell viability and IC50 values were assessed in cell lines by MTT assays after exposure to OTX015 (0.1nM-10µM) for 72h. Cell-cycle distribution was determined by cytofluorometric analysis detecting nuclear propidium iodide (PI) intercalation. Induction of apoptosis was evaluated in cell lines and patient cells by outer membrane phosphatidylserine exposure and PI incorporation at 72 hours with increasing doses of OTX015 (25nM-500nM). Caspase-3 activation and mitochondrial cytochrome c release were studied by immunofluorescence (IF). Maturation was assessed by morphological studies after MGG staining and detection of CD11b by FACS analysis. Modulation of BRD2/3/4 proteins was investigated by WB. Results OTX015 IC50 values were in the submicromolar range for KG1 and the MLL-driven NOMO1 cell lines (198.3 and 229.1nM, respectively), while K562 was the most resistant myeloid line, with an IC50 of 11.3µM. In contrast, in lymphoid cell lines tested, IC50 values ranged from 34.2 to 249.7nM, with the MLL-driven cell line RS4-11 being the most sensitive. Cell cycle arrest in subG1/G1 to S transition was observed in 8/9 cell lines and was most pronounced in RS4-11 and BV173. Significant apoptosis (up to 88% Annexin V positive cells) was only observed in KG1a and NOMO1 among myeloid cell lines, while OTX015 induced apoptosis in all lymphoid cell lines tested, ranging from 57% in RS4-11 to 90% in the BCR-ABL+ TOM1 cells. Similarly, OTX015 triggered caspase-dependent cell death, as NOMO1 and RS4-11 displayed significant caspase-3 activation and cytochrome c release, when compared to the resistant K562 cell line. Seven primary patient fresh samples (5 AML, 2ALL) were also analyzed. Ex vivo treatment induced apoptosis ranged from 35% to 87% in 6/7 patients. Exposure to OTX015 at 500nM for 7 days induced maturation in 51% and 65% of HL60 cells as detected by CD11b expression and morphology, respectively. Baseline expression of BRD2/3/4 varied among cell lines or patient samples, lower BRD2/3/4 expression levels were observed in the BCR-ABL+ K562 and BV173 cell lines, as well as in the 4 BCR-ABL+ ALL samples analyzed. Upon OTX015 exposure, down-regulation of the BRD4 target gene c-MYC was observed in all cell lines, without clear correlation with the proliferation inhibition rate and/or the intensity of induced apoptosis while no consistent BRD2/3/4 mRNAs down-regulation was seen. Interestingly, BRD2 protein was down-regulated in HL60, Jurkat and RS4-11 cell lines, but not in the K562 cell line. Conclusion OTX015 affects cell viability, induces cell cycle arrest in G1/S phase, and is able to induce significant apoptosis in leukemic cell lines and fresh AML and ALL samples at submicromolar drug concentrations. These concentrations were achieved in the serum of healthy volunteers after safe administration of the drug. With such characteristics, OTX015 appears to be an attractive anti-leukemic therapy, currently under early evaluation in a Phase Ib dose-escalation trial conducted in relapsed/refractory AML/ALL patients. Disclosures: Riveiro: Oncology Therapeutic Development: Employment. Herait:Oncoethix: Employment. Dombret:Oncoethix: Research Funding.
Dissertations / Theses on the topic "OTX015"
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Odore, Elodie. "Etude pharmacologique d’un nouvel inhibiteur de bromodomaines, l’OTX015, utilisé en cancérologie : Evaluation préclinique et clinique." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA114830.
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Malgré les progrès évidents sur la compréhension de la carcinogénèse, l’incidence des cancers est toujours en augmentation. C’est pourquoi les besoins en nouveaux traitements sont importants. Notre travail de thèse a porté sur l’évaluation pharmacologique d’une nouvelle molécule anticancéreuse, l’OTX015. Cette petite molécule de synthèse a la propriété d’inhiber les protéines bromodomaines (famille des BET) qui jouent un rôle clé dans les mécanismes épigénétiques et dont la dérégulation favorise l’apparition de cancers en particulier des hémopathies malignes. Des études précliniques in vitro sur plusieurs lignées cellulaires d’hémopathies malignes et in vivo sur des souris xénogreffées ont permis de mettre en évidence les propriétés antitumorales de l’OTX015. Une méthode de dosage des concentrations plasmatiques d’OTX015 par UPLC-MS/MS a été développée et validée afin d’évaluer sa pharmacocinétique chez les patients inclus dans un protocole d’escalade de doses de phase I. Dans un premier temps, la PK de l’OTX015 a été modélisée par une approche de population et dans un second temps un modèle PK-PD a été construit pour pouvoir évaluer le profil de la tolérance (nombreuses thrombopénies) de cette nouvelle moléculeDespite obvious progress in carcinogenesis understanding, the incidence of cancer is still increasing. Therefore, the need of new treatments remains important. Our thesis focused on the pharmacological evaluation of a new anticancer drug, OTX015. This small synthetic molecule inhibits the bromodomain proteins (BET) that play a key role in epigenetic mechanisms. Downregulation of BRDs promotes cancer occurrence including hematological malignancies. Preclinical evidences obtained from in vitro and in vivo studies in xenograft mice, suggest that OTX015 has antitumor properties. An ultra-performance liquid chromatography with tandem mass spectrometry detection method was developed and validated in order to measure OTX015 plasma concentrations. Its pharmacokinetics in patients enrolled in a phase I dose-escalation study was then evaluated. The OTX015 PK parameters were estimated by a population approach and PK-PD modeling was developed in order to evaluate the tolerance and safety (thrombocytopenia) of this new drug
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Ottaviani, Daniela. "In-Depth Characterization of Human Retinoblastoma Subtype 2 and Preclinical Models." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS001.
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Le rétinoblastome, un cancer pédiatrique de la rétine en développement, est la tumeur intraoculaire la plus fréquente chez l’enfant et représente environ 4 % de tous les cancers infantiles. Bien qu'il s'agisse d'une maladie rare, l'hôpital Curie (centre de référence pour le rétinoblastome en France) accueille environ 50 à 60 nouveaux patients chaque année. Notre groupe a précédemment caractérisé deux sous-types de rétinoblastomes. Les tumeurs de type « cone-like » ou sous-type 1 sont plutôt différenciées et homogènes, présentent une surexpression des gènes liés aux cellules cônes (photorécepteurs) de la rétine, sont diagnostiquées cliniquement plus tôt et regroupent la majorité des formes héréditaires et bilatérales. Les tumeurs « mixed-type » ou sous-type 2, présentent une hétérogénéité intra-tumorale et une surexpression des gènes liés aux cellules des cônes et des cellules ganglionnaires de la rétine, sont enrichies en patients unilatéraux qui sont diagnostiqués cliniquement à des âges plus avancés. Nous avons caractérisé le paysage moléculaire et génomique de 102 rétinoblastomes provenant de trois institutions : l'Institut Curie (France), l'Hôpital Garrahan (Argentine) et l'Hôpital Sant Joan de Déu (Espagne). Le développement d'une signature de méthylation par pyroséquençage pour la classification des échantillons nous a permis d'élargir nos échantillons classés, d'une première série de 72 à notre dernière série de 102 tumeurs. L'analyse du paysage mutationnel de notre série a révélé que les tumeurs du sous-type 2 avaient plus de mutations somatiques par échantillon que les tumeurs du sous-type 1. De plus les gènes BCOR et ARID1A étaient les deux seuls gènes mutés de manière récurrente, et identifiés uniquement dans le sous-type 2. En divisant notre cohorte de tumeurs en sous-type 1 et 2, la distribution des mutations le long de RB1 était significativement différente. Par ailleurs, nous avons identifié une région de la protéine RB1 (dans le Domaine A) enrichie en mutations provenant des tumeurs du sous-type 2, avec très peu de mutations du sous-type 1. En plus, nous avons caractérisé deux événements récurrents de fusion chromosomique perturbant le gène DACH1. Les tumeurs de sous-type 2 sont caractérisées par une surexpression de TFF1, non exprimée dans la rétine normale. L'analyse par immunohistochimie de TFF1 dans des tumeurs localement invasives provenant de l'hôpital Garrahan a révélé la présence de cellules TFF1+ envahissant la région rétrolaminaire du nerf optique. Nous avons exploré un possible rôle oncogène de TFF1 dans le rétinoblastome lié à la survie cellulaire, à la migration cellulaire et à l'invasion cellulaire, qui n'a finalement pas été mis en évidence in vitro. Le sous-type moléculaire 2 regroupe les tumeurs MYCN amplifiées et les tumeurs avec une activation de la voie de signalisation MYC et des gènes cibles de MYC. L'utilisation de JQ1 et OTX015 (inhibiteurs des protéines BET) a fortement réduit la viabilité in vitro de lignées cellulaires de rétinoblastomes représentatives du sous-type 2, avec une régulation négative significative du gène et de la protéine MYC/MYCN. Nos résultats préliminaires suggèrent une nouvelle piste thérapeutique par l'inhibition des protéines BET dans le rétinoblastome. Les modèles précliniques largement utilisés dans la recherche sur le rétinoblastome n'ont pas été caractérisés ou classés au niveau moléculaire. Nous avons utilisé la même approche que pour la classification des tumeurs primaires et avons constaté que la plupart des modèles cellulaires et PDX étudiés étaient classés dans le sous-type moléculaire 2 et partageaient des caractéristiques moléculaires, génomiques et protéiques trouvés dans les tumeurs primaires de ce sous-type moléculaire. En conclusion, nous avons pu caractériser de façon plus approfondie le sous-type 2 des rétinoblastomes, qui semble présenter un phénotype plus agressif et qui est le sous-type représenté dans les modèles précliniques analysésRetinoblastoma (RB) is a rare pediatric cancer of the developing retina that represents the most common intraocular tumor in children, and accounts for about 4% of all childhood cancers. Although being a rare disease, the Curie Hospital (the referral center for retinoblastoma in France) treats about 50-60 new patients each year. Our group has previously characterized two retinoblastoma subtypes. The cone-like or subtype 1 tumors rather differentiated and homogenous, presenting an overexpression of genes related to cone photoreceptor retinal cells, clinically diagnosed earlier and grouping the majority of hereditary and bilateral forms. The mixed-type or subtype 2 tumors, displaying an intra-tumoral heterogeneity and showing overexpression of genes related to cone and retinal ganglion cells, are enriched in unilateral patients clinically diagnosed at older ages. The general goal of my thesis was to extend the molecular characterization of these subtype 2 retinoblastomas. We characterized the molecular and genomic landscape of retinoblastoma in a series of 102 primary tumors, integrating samples from three institutions: the Curie Institute (France), the Garrahan Hospital (Argentina) and Sant Joan de Déu Hospital (Spain). The development of a pyrosequencing-based tool for sample classification allowed us to enlarge our classed samples, from an initial series of 72, to our final series of 102 tumors. Analysis of the mutational landscape in our series revealed that tumors from the subtype 2 had significantly more somatic mutations per sample than tumors from the subtype 1. Besides RB1 gene, BCOR and ARID1A where the only two recurrently mutated genes, and identified only in the subtype 2. Distribution of mutations alongside the RB1 gene has so far been analyzed in terms of a single group of retinoblastomas. When splitting our cohort in subtype 1 and subtype 2 tumors, the distribution of mutations was significantly different. Besides, we identified a region of the RB1 protein (in Domain A) enriched in mutations from tumors of the subtype 2, and devoid of mutations of the subtype 1. Besides somatic mutations, we characterized two recurrent chromosomal fusion events disrupting DACH1. Subtype 2 tumors are characterized by an overexpression of TFF1, not expressed in the normal retina. Immunohistochemical analysis of TFF1 in locally invasive tumors coming from the Garrahan Hospital revealed the presence of TFF1+ cells invading the retrolaminar region of the optic nerve. We then explored a possible oncogenic role of TFF1 in retinoblastoma related to cell survival, cell migration and cell invasion, which was not fully uncovered. Molecular subtype 2 regroups the MYCN amplified tumors and tumors with MYC signaling pathway activation and upregulation of hallmark MYC target genes. The use of JQ1 and OTX015 (BET bromodomains inhibitors) strongly reduced the viability in vitro of retinoblastoma cell lines representatives of the subtype 2, together with a significant MYC/MYCN gene and protein downregulation. We provided preliminary results to explore a new therapeutic avenue of BET protein inhibition in retinoblastoma. Preclinical models widely used in retinoblastoma research has not been characterized or classified at the molecular level. We have used the same approach as for primary human tumor’s classification, and found that most cellular and PDX models studied classed in the molecular subtype 2 and shared many of the molecular, genomic and protein characteristics found in primary tumors of this molecular subtype. Taken together, we have performed a deeper characterization of subtype 2 retinoblastomas, which seems to represent a more aggressive phenotype, and is the represented subtype in the preclinical models analyzed
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Bharathan, Navaneetha Krishnan. "THE ROLE OF THE RX3/ OTX PATHWAY IN ZEBRAFISH EYE DEVELOPMENT." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3346.
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Colobomas are a type of eye defect characterized by the presence of a hole in certain eye structures. In this study, the roles of the zebrafish Otx genes, otx2 and otx1a, as well as the Rx family gene, rx3, in choroid fissure closure, the disruption of which leads to the onset of colobomas, were studied. It was observed that while the otx2 loss-of-function mutant, otx2hu3237 displayed small colobomas and the otx1a mutant, otx1a6del, did not exhibit any morphological eye defects, zebrafish possessing both mutations presented with a range of colobomas, some of which were more severe than otx2 single mutants and the size of the coloboma corresponded with the gene dosage of otx1a. Furthermore, it was also observed that additional knockdown of otx1b using morpholinos worsened the coloboma phenotype. Moreover, it was observed that rx3, while involved in RPE pigmentation, does not contribute to choroid fissure closure. Additionally, it appears that otx2 does not affect the rudimentary lens formation which is seen in loss-of-function rx3 mutants, i.e., eyeless mutants.
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Muoio, Valeria Marques Figueira. "Análise molecular dos genes OTX1 e OTX2 em meduloblastomas." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-27082010-183238/.
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INTRODUÇÃO: O meduloblastoma, tumor maligno do Sistema Nervoso Central mais comum em crianças, foi inicialmente descrito de forma uniforme em 1925 por Bailey e Harvey Cushing. A despeito do avanço diagnóstico e terapêutico, os índices de morbimortalidade persistem altos. Grupos epidemiologicamente semelhantes podem ter desfechos diferentes, e evoluções desfavoráveis ocorrem em pacientes com marcadores de bom prognóstico. Os avanços nas pesquisas em biologia molecular procuram explicar os diferentes comportamentos da doença, e de forma sistemática, buscam identificar genes que sirvam como alvos terapêuticos, já que o tratamento disponível atualmente ainda é bastante insatisfatório e com muitos efeitos colaterais. Simeone e colaboradores identificaram os genes OTX1 e OTX2, presentes em humanos, e cuja função é organizar, compartimentalizar e hierarquizar a formação do sistema nervoso central, especialmente o cerebelo. Os genes OTX1 e OTX2 são expressos no tecido cerebelar em humanos até a nona semana de vida extra-uterina, exclusivamente. Os mesmos autores também identificaram que os mesmos genes são alvo terapêutico do ácido transretinóico, que inibe a expressão gênica. Estudos prévios demonstraram a expressão dos genes OTX1 e OTX2 em meduloblastomas, o que torna o ácido uma potencial terapêutica para estes tumores, assim como os genes OTX1 e OTX2 potenciais alvos para desenvolvimento de novas drogas terapêuticas. OBJETIVOS: Estudar a prevalência dos genes OTX1 e OTX2 em uma amostra de 60 pacientes, e estabelecer correlações entre a expressão gênica e aspectos clínicos, patológicos e de evolução. CASUÍSTICA E MÉTODO: Realizada análise retrospectiva de 60 pacientes com diagnóstico meduloblastoma, operados no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, e no Hospital do Câncer de Barretos. Organizado um banco de dados de 60 pacientes contendo dados da expressão gênica dos genes OTX1 e OTX2 (obtida através da técnica de PCR em tempo real) e dados clínico-epidemiológicos. Realizados testes estatísticos para se estabelecer correlação entre dados clínico-patológicos e de expressão gênica. RESULTADOS: O gene OTX1 foi expresso em 52% da população estudada, e tal expressão variou com a idade (sendo maior em adultos), localização (preferência por hemisfério) e tipo histológico (desmoplásico). O gene OTX2 foi expresso em 62% da população estudada, e tal expressão variou com a idade (sendo maior quanto menor a faixa etária), localização (preferência por vérmis) e tipo histológico (clássico). Houve correlação estatística entre a expressão do gene OTX2 e o desenvolvimento de metástases leptomeníngeas. CONCLUSÕES: Na população estudada, a expressão dos genes OTX1 e OTX2 corrobora a impressão de seu papel importante na patogênese dos meduloblastomas, e é dependente da idade do paciente, da localização tumoral e do tipo histológico. Dada a sensibilidade do gene ao ácido transretinóico, a identificação deste perfil populacional pode significar no futuro novas perspectivas de tratamento.INTRODUCTION: Medulloblastoma, the most common malignant tumor of the central nervous system in children, was first uniformly described in 1925 by Bailey and Harvey Cushing. Despite the diagnostic and therapeutic advances, the morbidity and mortality rates remain high. Epidemiologically similar groups may have different outcomes, and adverse developments occur in patients with markers of good prognosis. Advances in molecular biology research seeks to explain the different behaviors of the disease, and consistently seek to identify genes that serve as drug targets, since the treatment currently available is still unsatisfactory and with many side effects. Simeone and colleagues identified genes OTX1 and OTX2 in humans, and whose function is to organize, prioritize and compartmentalize the formation of the central nervous system, especially the cerebellum. OTX1 and OTX2 genes are expressed in cerebellar tissue in humans until the ninth week of extra uterine life, exclusively. The same authors also found that the same genes are therapeutic target of trans-retinoic acid, which inhibits gene expression. Previous studies have demonstrated the expression of OTX1 and OTX2 genes in medulloblastomas, which makes the acid a potential therapy for these tumors, as well as the genes OTX2 and OTX1 potential targets for developing new therapeutic drugs. OBJECTIVES: To study the prevalence of OTX1 and OTX2 genes in a sample of 60 patients, and to establish correlations between gene expression and clinical, pathological and follow up aspects. CASUISTICS AND METHODS: A retrospective analysis of 60 patients diagnosed with medulloblastoma, assisted at Hospital of the Faculty of Medicine, University of São Paulo, and the Cancer Hospital of Barretos. Organized a database of 60 patients which contains the gene expression of OTX1 and OTX2 genes (obtained through the technique of real-time PCR) and clinical and epidemiological data. Performed statistical tests to establish a correlation between clinical-pathological and gene expression. RESULTS: The OTX1 gene was expressed in 52% of the population studied, and such expression varied with age (being higher in adults), location (preferably by hemisphere) and histology (desmoplastic). The OTX2 gene was expressed in 62% of the studied population, and such expression varied with age (being higher the younger the age group), location (preferably vermis) and histological type (classical). A statistical correlation between the expression of OTX2 gene and development of leptomeningeal metastases was observed. CONCLUSIONS: In the studied population, the expression of OTX1 and OTX2 genes corroborates the impression of his role in the pathogenesis of medulloblastomas, and is dependent on patient age, tumor location and histological type. Given the sensitivity of the gene-trans retinoic acid, the identification of the population profile in the future will represent new opportunities for treatment.
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Giuliani, Giuliano. "The role of TBX1 and OTX1 in the development of the zebrafish inner ear." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548543.
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Noche, Ramil Romare. "In Vivo Analysis of Zebrafish Exo-rhodopsin Protein and Suprachiasmatic Nucleus Function." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1212772912.
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Pierce, Lain Xylia. "Analysis of Rhythmic Gene Transcription using the TimeR, a Novel Technology to Capture Zebrafish Embryos." Cleveland, Ohio : Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1212770242.
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COEN, LAURENT. "Construction de nouvelles molecules genetiques qui migrent de maniere retrograde et transynaptique dans le systeme nerveux central. Application au gene otx1 implique dans le developpement du cerveau anterieur chez la souris." Paris 6, 1997. http://www.theses.fr/1997PA066279.
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Les neurones etablissent des circuits specifiques et complexes par des reseaux de cellules interconnectees, destines a transmettre des informations pour assurer la bonne cohesion des fonctions de l'organisme. Comme pour l'ensemble des cellules de l'organisme, le bon fonctionnement des cellules neuronales est assure par un programme genetique precis et specifique du type cellulaire ou il se deroule. Si un gene s'exprimant dans une cellule neuronale donnee est mute, il est probable que cette mutation affectera les fonctions des autres neurones interconnectes. La technique de recombinaison homologue, remplacant specifiquement le gene d'interet par le gene rapporteur lacz, permet la visualisation des cellules mutees mais pas des connexions neuronales etablies par cette cellule. Nous avons donc cherche a developper une nouvelle classe de marqueurs adaptee a l'etude des connexions neuronales in vivo chez la souris. Ainsi, l'expression d'un tel marqueur transynaptique dans un neurone particulier permettrait d'obtenir des informations relatives aux interractions qui s'etablissent entre ce neurone et les autres neurones connectes. Le fragment ttc non toxique, derive de la toxine tetanique, possede des proprietes de transport retrograde et transneuronal similaires a la toxine entiere. L'utilisation du gene rapporteur lacz fusionne au fragment ttc a permis de developper deux molecules hybrides, -gal-ttc et ttc--gal, reperables par leur activite -galactosidase et internalisees efficacement dans les neurones en culture. Nous demontrons dans une etude in vivo, par injection de la proteine -gal-ttc dans la langue d'une souris, que le fragment ttc est capable de transporter l'activite -galactosidase dans des regions variees du systeme nerveux central. En effet, apres son internalisation au niveau de la jonction neuromusculaire, la proteine hybride remonte jusqu'aux corps cellulaires des motoneurones du noyau hypoglossal par un mecanisme specifique de transport axonal retrograde. Elle est ensuite distribuee par transfert transynaptique aux interneurones qui etablissent des synapses avec ces motoneurones. Nous avons utilise ce nouveau marqueur genetique lacz-ttc pour initier une etude des connexions neuronales etablies par les neurones exprimant le gene otx1. Ce gene est implique dans la formation du systeme nerveux dans la partie anterieure du cerveau et il est probable que sa mutation entraine un dereglement des connexions synaptiques responsable du phenotype epileptique des souris mutantes otx1-/-.
Book chapters on the topic "OTX015"
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Mak, Tak W., Josef Penninger, John Roder, Janet Rossant, and Mary Saunders. "Otx1." In The Gene Knockout FactsBook, 835–36. Elsevier, 1998. http://dx.doi.org/10.1016/b978-012466044-1/50460-9.
Full textConference papers on the topic "OTX015"
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Noel, J. Kay, Kazunori Iwata, Shinsuke Ooike, Kunio Sugahara, Hideo Nakamura, and Masanori Daibata. "Abstract C244: Development of the BET bromodomain inhibitor OTX015." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-c244.
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Gaudio, Eugenio, Chiara Tarantelli, Filippo Spriano, Alberto J. Arribas, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, and Francesco Bertoni. "Abstract 1894: Identification of novel OTX015-containing combinations for lymphoma treatment." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1894.
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Todaro, Maria, Michela Boi, Valentina Vurchio, Elisabetta Ercole, Rodolfo Machiorlatti, Katia Messana, Indira Landra, et al. "Abstract 5531: OTX015, a novel BET inhibitor, is a promising anticancer agent for multiple myeloma." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-5531.
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Civenni, Gianluca, Silvia Pedrani, Sara Allegrini, Antonina Bruccoleri, Domenico Albino, Sandra Pinton, Ramon Garcia-Escudero, et al. "Abstract 2625: Targeting prostate cancer stem cells (CSCs) with the novel BET bromodomain (BRD) protein inhibitor OTX015." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2625.
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Bonetti, Paola, Michela Boi, Elena Bernasconi, Andrea Rinaldi, Ivo Kwee, Eugenio Gaudio, Maurilio Ponzoni, et al. "Abstract 1017: The BRD-inhibitor OTX015 affects proliferation and gene expression of cells derived from mature lymphoid neoplasms." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-1017.
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Odore, Elodie, Keyvan Rezai, Eugenia Riveiro, Fabrice Bourdel, Patrice Herait, Esteban Cvitkovic, Herve Dombret, and Francois Lokiec. "Abstract LB-231: A phase I pharmacokinetic study of OTX015 for the treatment of patients with hematologic malignancies." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-lb-231.
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Schulte, Johannes H., Kristina Althoff, Emma Bell, Andrea Odersky, Anneleen Beckers, Frank Speleman, Simon Schäfers, et al. "Abstract 3967: BET protein inhibitor OTX015 has selective anti-tumoral activity in preclinical models of MYCN- amplified neuroblastoma." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3967.
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Maser, Tyler P., Joseph W. Zagorski, Austin J. Goodyke, Elizabeth A. VanSickle, Jeffrey P. Bond, and Giselle L. Saulnier Sholler. "Abstract 3191: The MDM2 inhibitor CGM097 synergizes with the BET inhibitor OTX015 to induce cell death in neuroblastoma cells." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3191.
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Boi, Michela, Maria Todaro, Valentina Vurchio, Esteban Cvitkovic, Eugenia Riveiro, Francesco Bertoni, and Giorgio Inghirami. "Abstract A219: OTX015, a bromodomain and extraterminal inhibitor, represents a novel agent for ALK positive anaplastic large cell lymphoma." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a219.
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Henssen, Anton, Kristina Althoff, Richard Koche, Andrea Odersky, Anneleen Beckers, Frank Speleman, Simon Schäfers, et al. "Abstract 4731: Targeting super-enhancer induced gene expression with the novel BRD4 inhibitor OTX015 in preclinical models of MYCN-amplified neuroblastoma." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-4731.
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