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Ivo Kwee - One of the best experts on this subject based on the ideXlab platform.
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Preclinical evaluation of the BET Bromodomain Inhibitor BAY 1238097 for the treatment of lymphoma.
British journal of haematology, 2017Co-Authors: Elena Bernasconi, Eugenio Gaudio, Chiara Tarantelli, Luciano Cascione, Andrea Rinaldi, Ivo Kwee, Afua Adjeiwaa Mensah, Pascale Lejeune, Filippo Spriano, Elaine ChungAbstract:Summary The epigenome is often deregulated in cancer and treatment with Inhibitors of Bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel Bromodomain and extra-terminal (BET) Inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% Inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain Inhibitors and partially overlapped with HDAC-Inhibitors, mTOR Inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK Inhibitors. In conclusion, the BET Inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET Bromodomains.
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the Bromodomain Inhibitor otx015 mk 8628 exerts anti tumor activity in triple negative breast cancer models as single agent and in combination with everolimus
Oncotarget, 2017Co-Authors: Ramiro Vázquez, Elodie Odore, Keyvan Rezai, Andrea Rinaldi, Ivo Kwee, Nicolò Panini, Eugenio Erba, Lucile Astorguesxerri, Maria E RiveiroAbstract:Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-Bromodomain Inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR Inhibitor everolimus in different models. The aim of this study was to evaluate the anti-tumor activity of OTX015 as single agent and in combination with everolimus in TNBC models. OTX015 was assayed in three human TNBC-derived cell lines, HCC1937, MDA-MB-231 and MDA-MB-468, all showing antiproliferative activity after 72 h (GI50 = 75-650 nM). This was accompanied by cell cycle arrest and decreased expression of cancer stem cells markers. However, c-MYC protein and mRNA levels were only down-regulated in MDA-MB-468 cells. Gene set enrichment analysis showed up-regulation of genes involved in epigenetic control of transcription, chromatin and the cell cycle, and down-regulation of stemness-related genes. In vitro, combination with everolimus was additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In MDA-MB-231 murine xenografts, tumor mass was significantly (p < 0.05) reduced by OTX015 with respect to vehicle-treated animals (best T/C = 40.7%). Although everolimus alone was not active, the combination was more effective than OTX015 alone (best T/C = 20.7%). This work supports current clinical trials with OTX015 in TNBC (NCT02259114).
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therapeutic efficacy of the Bromodomain Inhibitor otx015 mk 8628 in alk positive anaplastic large cell lymphoma an alternative modality to overcome resistant phenotypes
Oncotarget, 2016Co-Authors: Michela Boi, Andrea Rinaldi, Ivo Kwee, Maria Todaro, Valentina Vurchio, Shao Ning Yang, John Moon, Heng Pan, Ramona Crescenzo, Mangeng ChengAbstract:// Michela Boi 1, 2, * , Maria Todaro 1, 2, * , Valentina Vurchio 1 , Shao Ning Yang 3 , John Moon 3 , Ivo Kwee 4, 5, 6 , Andrea Rinaldi 4 , Heng Pan 7, 8 , Ramona Crescenzo 1, 2 , Mangeng Cheng 9 , Leandro Cerchietti 3 , Olivier Elemento 7, 8 , Maria E. Riveiro 10 , Esteban Cvitkovic 10, 11 , Francesco Bertoni 4, 12 , Giorgio Inghirami 1, 2, 13 , The AIRC 5xMille Consortium ‘Genetics-Driven Targeted Management of Lymphoid Malignancies’ 1 Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy 2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA 3 Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA 4 Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland 5 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland 6 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland 7 Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA 8 Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA 9 In Vitro Pharmacology, Merck Research Laboratory, Boston, MA, USA 10 Oncology Therapeutic Development, Clichy, France 11 Oncoethix SA (Now Oncoethix GmbH, A Wholly Owned Subsidiary of Merck Sharp & Dohme Corp.), Lucerne, Switzerland 12 IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland 13 Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Giorgio Inghirami, email: ggi9001@med.cornell.edu Francesco Bertoni, email: frbertoni@mac.com Keywords: anaplastic large cell lymphoma, BRD Inhibitor, OTX015/MK-8628, tyrosine kinase Inhibitor, gene expression profiling Received: July 07, 2016 Accepted: September 19, 2016 Published: October 25, 2016 ABSTRACT Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel Bromodomain Inhibitor, OTX015/MK-8628 in ALK-positive ALCLs. The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies. Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with Bromodomain Inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors ( E2F2 , NFKBIZ, FOS , JUNB, ID1, HOXA5 and HOXC6 ) , members of multiple signaling pathways ( ITK , PRKCH, and MKNK2 ), and histones (clusters 1-3). Combination of OTX015 with the Bruton’s tyrosine kinase (BTK) Inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK Inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 Inhibitor, C1156Y-resistant ALK ALCL growth was impaired. These findings support OTX015 clinical trials in refractory ALCL in combination with Inhibitors of interleukin-2-inducible kinase or SHH/GLI1.
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Assessment of the Antiproliferative Activity of a BET Bromodomain Inhibitor as Single Agent and in Combination in Non-Hodgkin Lymphoma Cell Lines.
Methods in molecular biology (Clifton N.J.), 2016Co-Authors: Elena Bernasconi, Eugenio Gaudio, Ivo Kwee, Francesco BertoniAbstract:To evaluate the antiproliferative activity of a novel BET Bromodomain Inhibitor as single agent and in combination with the BTK Inhibitor ibrutinib in non-Hodgkin lymphoma cell lines, we performed the MTT proliferation assay. This assay is based on the direct correlation between absorbance (measured colorimetrically at a wavelength of 570 nm) and cell proliferation. Thiazolyl Blue Tetrazolium Blue (MTT) is a yellowish solution that distinguishes between proliferating and dead cells since it is converted to water-insoluble MTT-formazan of dark blue color by mitochondrial dehydrogenases of living cells only.
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the bet Bromodomain Inhibitor otx015 affects pathogenetic pathways in preclinical b cell tumor models and synergizes with targeted drugs
Clinical Cancer Research, 2015Co-Authors: Michela Boi, Eugenio Gaudio, Chiara Tarantelli, Elena Bernasconi, Luciano Cascione, Andrea Rinaldi, Ivo Kwee, Paola Bonetti, Monica Testoni, Maurilio PonzoniAbstract:Purpose: In cancer cells, the epigenome is often deregulated, and inhibition of the Bromodomain and extra-terminal (BET) family of Bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET Bromodomain Inhibitor OTX015. Experimental Design: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound. Results: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC 50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK Inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell–like diffuse large B-cell lymphoma, bearing wt TP53 , mutations in MYD88 , and CD79B or CARD11 . Conclusions: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies. Clin Cancer Res; 21(7); 1628–38. ©2015 AACR .
Matteo Vecellio - One of the best experts on this subject based on the ideXlab platform.
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cbp30 a selective cbp p300 Bromodomain Inhibitor suppresses human th17 responses
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: A Hammitzsch, O Fedorov, C Tallant, Alison Omahony, Paul Brennan, Duncan Hay, Fernando O Martinez, Hussein Almossawi, Jelle De Wit, Matteo VecellioAbstract:Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective Bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the Bromodomains of CBP and p300, compared with 43 other Bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) Bromodomain Inhibitor JQ1. This selective targeting of the CBP/p300 Bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic Inhibitors currently in clinical trials.
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CBP30, a selective CBP/p300 Bromodomain Inhibitor, suppresses human Th17 responses
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: A Hammitzsch, O Fedorov, C Tallant, Duncan Hay, Fernando O Martinez, Jelle De Wit, Alison O'mahony, Paul E. Brennan, Hussein Al-mossawi, Matteo VecellioAbstract:Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective Bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the Bromodomains of CBP and p300, compared with 43 other Bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) Bromodomain Inhibitor JQ1. This selective targeting of the CBP/p300 Bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic Inhibitors currently in clinical trials.
Lisa Bauman - One of the best experts on this subject based on the ideXlab platform.
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abstract ct095 a phase ib iia study of the bet Bromodomain Inhibitor zen 3694 in combination with enzalutamide in patients with metastatic castration resistant prostate cancer mcrpc
Clinical Trials, 2019Co-Authors: Rahul Aggarwal, Michael T Schweizer, Sanjay Lakhotia, Wassim Abida, Elisabeth I. Heath, Henrik Hansen, Allan J Pantuck, Michael Silverman, David M Nanus, Lisa BaumanAbstract:Background: Abiraterone (ABI) and enzalutamide (ENZ) have significant activity in mCRPC yet demonstrate frequent cross-resistance limiting efficacy of sequential androgen receptor (AR) targeting. Bromodomain extra terminal (BET) Inhibitors (BETi) down-regulate the expression of putative drivers of ABI/ENZ resistance. ZEN-3694 is an orally bioavailable, potent, and selective BETi with significant anti-tumor activity in ENZ-resistant pre-clinical models. The safety and efficacy of ZEN-3694 in combination with ENZ was evaluated in a phase 1b/2a study in mCRPC (NCT02711956). Methods: Patients (pts) were required to have progressive mCRPC, prior resistance to ABI and/or ENZ, and no prior chemotherapy for mCRPC. A 3 plus 3 dose escalation schema was utilized, with a starting daily oral dose of ZEN-3694 36 mg plus ENZ 160 mg. Dose expansion was conducted in parallel cohorts at low and high-dose ZEN-3694 (48 and 96 mg daily, respectively). The primary objective was determination of maximally tolerated dose (MTD); key secondary endpoints included time to radiographic progression (TTP) and pharmacokinetic (PK) parameters. Pharmacodynamic (PD) markers included whole blood RNA expression of BETi targets including MYC, IL-8, CCR1, and IL1RN. Results: 64 pts were enrolled. The median age and PSA at study entry was 70 (range 47 - 89) and 25.9 (range 0.1 - 1701.8), respectively. At study entry, 24 (37.5%) of pts were resistant to ABI, 29 (45.3%) were resistant to ENZ, and 11 (17.2%) to both. ZEN-3694 dose levels ranged from 36 mg to 144 mg daily without reaching a MTD. The most common treatment-related adverse events (AEs) (any grade) included transient photophobia (66%), nausea (40%), fatigue (31%), decreased appetite (22%), and dysgeusia (16%). Grade ≥ 3 related AEs (N = 8) and dose-limiting toxicities (N = 1 at 96 mg dose level) were uncommon. No Grade ≥ 3 thrombocytopenia was observed. Exposure to ZEN-3694 increased with dose without significant drug-drug interaction with ENZ. PD analyses demonstrated exposure-dependent, up to 4-fold decrease in expression of BETi targets. RNA-Seq of paired tumor biopsies demonstrated suppression of BET-dependent genes. The overall median TTP was 44.4 weeks, and was similar in subgroups with prior ABI vs. ENZ resistance. Durable responses were observed, including 3 pts with disease primarily refractory to ABI on study treatment for 21.3 +, 20.8 +, and 17.3 months, respectively, with > 90% decline in serum PSA. Early transitory serum PSA increases were associated with longer TTP. Conclusions: ZEN-3694 demonstrates an acceptable safety and PK profile, robust target modulation, and encouraging disease stabilization in combination with ENZ in ABI/ENZ-refractory mCRPC. Analysis of paired metastatic tumor biopsies, circulating tumor cells and ctDNA is ongoing. Further investigation of the combination is warranted. Citation Format: Rahul Aggarwal, Wassim Abida, Michael Schweizer, Allan Pantuck, David Nanus, Elisabeth Heath, Sanjay Lakhotia, Henrik Hansen, Michael Silverman, Lisa Bauman, Margo Snyder, Eric Campeau, Karen Norek, Sarah Attwell, Marie O9Farrell, Steve Smith, Philip Wegge, Ravi Jahagirdar, Joshi Alumkal. A Phase Ib/IIa study of the BET Bromodomain Inhibitor ZEN-3694 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT095.
Holly M Nguyen - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 207 preclinical characterization of zen 3694 a novel bet Bromodomain Inhibitor entering phase i studies for metastatic castration resistant prostate cancer mcrpc
Cancer Research, 2016Co-Authors: Sarah Attwell, Ravi Jahagirdar, Karen Norek, Cyrus Calosing, Laura Tsujikawa, Olesya A Kharenko, Reena G Patel, Emily M Gesner, Eva Corey, Holly M NguyenAbstract:Metastatic castration resistant prostate cancer (mCRPC) is a major unmet medical need due to its widespread occurrence and incurable status. Current standard of care for advanced prostate cancer is androgen-deprivation therapy (ADT), and upon failure, patients are administered secondary ADT with androgen receptor (AR) antagonists such as enzalutamide and abiraterone. While most patients display an initial response to these agents, eventually all become resistant via various mechanisms that often result in constitutive AR signaling including mutations of the AR, and the generation of AR splice variants that bypass the ligand binding domain. Other mechanisms of resistance to AR antagonists include up-regulation of the glucocorticoid receptor (GR), and partial to complete loss of AR signaling through neuroendocrine differentiation. Recent evidence suggests that BET Bromodomain Inhibitors (BETi) could be efficacious in AR-signaling positive or negative mCRPC that are resistant to current therapies. ZEN-3694 is an orally bioavailable, potent BETi that selectively binds to both Bromodomains of the BET proteins. In vitro, ZEN-3694 has demonstrated strong activity against several prostate cancer cell lines with submicromolar potency, including AR positive and AR negative, neuroendocrine, and enzalutamide resistant cell lines. In VCaP AR-positive prostate cancer cells, ZEN-3694 inhibited proliferation synergistically with enzalutamide, resulting in potent up-regulation of the CDKN1C/KIP2 tumor suppressor gene. In 22Rv1 cells displaying constitutive AR signaling through the AR-V7 splice variant, ZEN-3694 inhibited AR signaling, and in an in vitro LNCaP model of acquired resistance to enzalutamide characterized by GR up-regulation, ZEN-3694 decreased levels of GR in a dose-dependent manner. Furthermore, in the PC3 AR-null cell line, the expression of a subset of NF-KB-dependent genes reported to be involved in mCRPC bone metastasis was found to be inhibited by ZEN-3694. In vivo, using multiple prostate cancer cell line xenografts such as 22Rv1, and VCaP, ZEN-3694 showed efficacy in inhibiting tumor progression at well-tolerated doses, and modulating target gene expression. ZEN-3694 also inhibited progression of a patient-derived xenograft (PDX) LuCaP 35CR that is resistant to enzalutamide. In summary, our results indicate that ZEN-3694 demonstrates potent activity in advanced metastatic prostate cancer targeting multiple mechanisms of enzalutamide resistance in CRPC, including AR-V7 signaling and GR up-regulation in different preclinical models. This together supports the clinical development of ZEN-3694 as a single agent, and in combination with enzalutamide in mCRPC patients that have failed first line ADT. We are implementing a robust translational medicine program in the phase 1 study to measure target engagement and explore mechanisms of enzalutamide resistance and sensitivity to ZEN-3694 in patients. Citation Format: Sarah Attwell, Ravi Jahagirdar, Karen Norek, Cyrus Calosing, Laura Tsujikawa, Olesya A. Kharenko, Reena G. Patel, Emily M. Gesner, Eva Corey, Holly M. Nguyen, Sanjay Lakhotia, Henrik C. Hansen, Eric Campeau. Preclinical characterization of ZEN-3694, a novel BET Bromodomain Inhibitor entering phase I studies for metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-207.
Sarah R Walker - One of the best experts on this subject based on the ideXlab platform.
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inhibiting stat5 by the bet Bromodomain Inhibitor jq1 disrupts human dendritic cell maturation
Journal of Immunology, 2015Co-Authors: Suhu Liu, Sarah R Walker, Patricia A Toniolo, Jennifer E Yeh, Pedro M MoraesvieiraAbstract:Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective Inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-12. The activation of STAT5 in Mo-DCs is mediated by GM-CSF produced following LPS stimulation. Activated STAT5 then leads to increased expression of both GM-CSF and GM-CSFR, triggering an autocrine loop that further enhances STAT5 signaling and enabling Mo-DCs to acquire a more mature phenotype. JQ1 decreases the ability of Mo-DCs to induce allogeneic CD4(+) and CD8(+) T cell proliferation and production of proinflammatory cytokines. Furthermore, JQ1 leads to a reduced generation of inflammatory CD8(+) T cells and decreased Th1 differentiation. Thus, JQ1 impairs LPS-induced Mo-DC maturation by inhibiting STAT5 activity, thereby generating cells that can only weakly stimulate an adaptive-immune response. Therefore, JQ1 could have beneficial effects in treating T cell-mediated inflammatory diseases.
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targeting stat5 in hematologic malignancies through inhibition of the Bromodomain and extra terminal bet Bromodomain protein brd2
Molecular Cancer Therapeutics, 2014Co-Authors: Suhu Liu, James E. Bradner, Sarah R Walker, Erik A Nelson, R Cerulli, Michael Xiang, Patricia A Toniolo, Richard Stone, Martha Wadleigh, David A FrankAbstract:The transcription factor signal transducer and activator of transcription 5 (STAT5) is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematological malignancies. Given the importance of Bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacological Bromodomain Inhibitor could inhibit STAT5-dependent gene expression. We found that the small molecule Bromodomain and extra-terminal (BET) Bromodomain Inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET Bromodomain sub-family of proteins, it appears that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knock-down or JQ1 treatment shows strong synergy with tyrosine kinase Inhibitors in inducing leukemia cells apoptosis. By contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and tyrosine kinase Inhibitors may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.
