scholarly journals Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma

eJHaem ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 122-132
Author(s):  
Pallawi Torka ◽  
Cory Mavis ◽  
Shalin Kothari ◽  
Sarah Belliotti ◽  
Juan Gu ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Enzyme Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Clinical Models ◽  
Large B Cell

scholarly journals Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth

2013 ◽  
Vol 20 (11) ◽  
pp. 1329-1339 ◽  
Author(s):  
Shivani Garapaty-Rao ◽  
Christopher Nasveschuk ◽  
Alexandre Gagnon ◽  
Eric Y. Chan ◽  
Peter Sandy ◽  
...  
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients

2016 ◽  
Vol 8 (1) ◽  
Author(s):  
Benet Pera ◽  
Tiffany Tang ◽  
Rossella Marullo ◽  
Shao-Ning Yang ◽  
Haelee Ahn ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Epigenetic Therapy ◽  
Large B Cell Lymphoma ◽  
Clinical Models ◽  
Large B Cell

An Orally Available Small Molecule BCL6 Inhibitor Effectively Suppresses Diffuse Large B Cell Lymphoma Cells Growth in Vitro and in Vivo

2021 ◽  
Author(s):  
Yajing Xing ◽  
Weikai Guo ◽  
Min Wu ◽  
Jiuqing Xie ◽  
Dongxia Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Small Molecule ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. Methods: We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. The binding affinity between WK500B and BCL6 was evaluated by surface plasmon resonance (SPR) assay and the binding mode of WK500B and BCL6 was predicted by molecular docking. The function evaluation and anti-cancer activity of WK500B in vitro and in vivo was detected by immunofluorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzyme-linked immunosorbent assay (ELISA), germinal centre (GC) formation mouse model and mouse xenograft model. Results: WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal centre formation and DLBCL tumor growth without toxic and side effects. Moreover, WK500B showed favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. Conclusions: WK500B showed strong efficacy and favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. So, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

Differential JAK-STAT Pathway Activation in Primary Mediastinal Large B-Cell Lymphoma: Two Subgroups with Differential Cytokine Activation Patterns and Predicted Responses to Kinase Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 968-968
Author(s):  
Dan Jones ◽  
Justin Windham ◽  
Brian Stewart ◽  
Luis Fayad ◽  
Alma Rodriguez ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Cell Lymphoma ◽  
Growth Parameters ◽  
B Cell Lymphoma ◽  
Activation Patterns ◽  
Large B Cell Lymphoma ◽  
Pathway Activation ◽  
Large B Cell ◽  
Stat Pathway

Abstract Abstract 968 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a specialized type of diffuse large B-cell lymphoma which shows diagnostic and pathogenetic overlap with mediastinal classical Hodgkin lymphoma. Approximately 60% of patients with PMBCL have good response to conventional chemoradiotherapy with the rest often showing distant relapses. Microarray studies of PMBCL have revealed overexpression of components and targets of the JAK-STAT signaling pathways including upregulation of IL13 receptor and STAT1; a subset of PMBCL have genome amplification of JAK2 or deletion of the JAK suppressor SOCS1. Given this complexity, we examined the most common mechanism and effects of JAK-STAT dysregulation in a series of newly diagnosed and recurrent PMBCL. Methods: Fifty-three biopsies from 23 patients with PMBCL were assessed and correlated with outcome. JAK2 and SOCS1 copy number status were determined by quantitative PCR on genomic DNA. JAK-STAT pathway activation was probed using reverse transcription quantitative (RQ)-PCR for JAK2, JAK3, and a panel of IL-4 and IL-13 transcriptional targets. JAK-STAT activation was assessed in tissue arrays using antisera against phospho-activation epitopes of STAT1, STAT3, STAT5, and STAT6 using immunohistochemistry (IHC). Activation patterns were modeled in the PMBCL cell line Karpas (K)1106P at baseline and following IL-4 and IL-13 stimulation with or without a range of small molecule inhibitors and blocking antibodies. Growth parameters were measured by MTT and protein levels by flow cytometry, Western blot, RQ-PCR and kinase profiling. Results: JAK2 genomic amplification was present in 40% of PMBCL and SOCS1 deletion in 10% as well as in the K1106P line. By phospho-activation IHC, tumors in 20/23 (87%) patients showed STAT activation, mostly due to STAT1 (60.8%) followed by STAT3 (26.1%), with 6 cases showing mixed patterns. In different tumors, localized and uniform STAT activation patterns were seen. Constitutive STAT activation was correlated with high expression of IL-4 transcription targets including CCL17 and IL13RA as well as JAK2 autophosphorylation and inferior outcome (p = .007). Tumors with more localized foci of activation were associated with alternate transcription patterns. In the K1106P cell line, IL-4 but not IL-13 treatment led to inducible STAT1 activation whereas baseline STAT3/6 activation was highly regulated by cytokine exposure. The JAK2 inhibitor JSI124 blocked IL-4 induced STAT1 activation whereas the JAK inhibitors AG-490, NSC7908 and WHI-P154 did not but did block IL-4/IL-13-induced STAT3 activation. The JAK3 inhibitor ZM39923 was most effective in blocking cell growth but did not block STAT1 activation. Conclusions: JAK2-STAT pathway activation characterizes nearly all cases of PMBCL but genetic mechanisms are distinct leading to distinct patterns of STAT1 activation (driven predominantly through the type I IL-4 receptor) and STAT3/6 activation (driven predominantly through the type II IL13RA/IL4RA) with differential effects on growth parameters and gene regulation. The patterns of STAT activation and target gene expression in primary tumors comprising these two groups mirrored the response to small molecule inhibitors following cytokine exposure in vitro in the K1106P line and highlights differences between IL-4 and IL-13 signaling in PMBCL. Profiling of PMBCL biopsies with phosphoactivation IHC for STAT isoforms may be useful to subcategorize cases and select the optimal JAK-STAT pathway inhibitors for adjuvant therapy. Disclosures: No relevant conflicts of interest to declare.

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

2012 ◽  
Vol 11 (9) ◽  
pp. 2045-2053 ◽  
Author(s):  
Judy Quiju Shi ◽  
Kerri Lasky ◽  
Vaishali Shinde ◽  
Bradley Stringer ◽  
Mark G. Qian ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Human Models ◽  
Large B Cell

A Small Molecule PLK1 Inhibitor, MLN0905, Induces An Anti-Tumor Response In Human Models of Diffuse Large B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3922-3922
Author(s):  
Judy Shi ◽  
Kerri Lasky ◽  
Vashali Shinde ◽  
Matt O Duffey ◽  
Bradley Stringer ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Cell Lymphoma ◽  
Human Tumor ◽  
B Cell Lymphoma ◽  
Survival Advantage ◽  
Mitotic Kinase ◽  
Large B Cell Lymphoma ◽  
Anti Tumor Activity ◽  
Large B Cell

Abstract Abstract 3922 Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30 percent of newly diagnosed cases. Current treatment options for this disease are effective, but not always curative; therefore experimental therapies are being investigated. Diffuse large B-cell lymphoma cells typically over-express the serine/threonine mitotic kinase PLK1, which plays a key role in mitotic cell cycle progression, and has been linked to poor patient prognosis. We have discovered a potent and selective small molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL lines. We explored the pharmacokinetic, pharmacodynamic, and anti-tumor properties on MLN0905 in mouse models harboring human DLBCL disease. MLN0905 has drug-like pharmacokinetic properties and an acceptable toxicity profile making it a good clinical candidate. In human xenograft tumor tissue, MLN0905 modulates the pharmacodynamic biomarker phospho-Histone H3 (in a dose dependent fashion), enabling us to track pathway modulation in vivo. The anti-tumor activity of MLN0905 was evaluated in three human subcutaneous xenograft models OCI-LY10, OCI-LY19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant anti-tumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The anti-tumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI-LY19) setting to better mimic DLBCL in humans. In this disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with Rituximab in the disseminated OCI-LY19 model. Combining Rituximab and MLN0905 provided both a synergistic anti-tumor effect and a synergistic survival advantage. Our findings indicate for the first time that PLK1 inhibition leads to pharmacodynamic pH3 modulation and significant anti-tumor activity in multiple models of DLBCL. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anti-cancer agents in the clinic. Disclosures: Shi: Millennium: The Takeda Oncology Company: Employment. Lasky:Millennium: The Takeda Oncology Company: Employment. Shinde:Millennium: The Takeda Oncology Company: Employment. Duffey:Millennium: The Takeda Oncology Company: Employment. Stringer:Millennium: The Takeda Oncology Company: Employment. Qian:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Liu:Millennium: The Takeda Oncology Company: Employment. Rao:Millennium: The Takeda Oncology Company: Employment. Vos:Millennium: The Takeda Oncology Company: Employment. D'Amore:Millennium: The Takeda Oncology Company: Employment. Hyer:Millennium: The Takeda Oncology Company: Employment.

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