Dataset Information

NEMO-binding domain peptide inhibits constitutive NF-?B activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.

ABSTRACT: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-?B activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-?B target genes. Inhibition of the canonical NF-?B pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-?B activity and to determine the therapeutic relevance of NF-?B inhibition in dogs with relapsed, resistant DLBCL.Canonical NF-?B activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-?B target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-?B essential modulator-binding domain (NBD) peptide and evaluated for NF-?B activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-?B target gene expression and tumor burden were evaluated pre- and post-treatment.Constitutive canonical NF-?B activity and increased NF-?B target gene expression were detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intratumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-?B target gene expression and reduced tumor burden.This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and shows the therapeutic relevance of NF-?B inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients.

SUBMITTER: Gaurnier-Hausser A

PROVIDER: S-EPMC3273413 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.

Gaurnier-Hausser Anita A Patel Reema R Baldwin Albert S AS May Michael J MJ Mason Nicola J NJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20110524 14

<h4>Purpose</h4>Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-κB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-κB target genes. Inhibition of the canonical NF-κB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant consti ...[more]

PMID: 21610150

Similar Datasets

Project description:IntroductionRelapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) has poor clinical outcomes when treated with conventional salvage chemotherapy. Monotherapy using zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has achieved modest antitumor effect in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of zanubrutinib plus salvage chemotherapy in R/R DLBCL patients.MethodsWe retrospectively reviewed R/R DLBCL patients who were administered with zanubrutinib plus salvage chemotherapy in our center between January, 2019 and December, 2021. Targeted panel sequencing of 11 lymphoma-related genes was performed on 8 patients with poor responses to zanubrutinib-based chemotherapy.Results27 R/R DLBCL patients were enrolled. Median age at this study was 59 years (range, 15-72). The best overall response rate (ORR) was 74.1% and complete remission rate was 33.3%. With a median follow-up of 11 months (range, 1-17), the median progression-free survival (PFS) was 8.1 months, and the overall survival (OS) was not achieved. The most common grade-3/4 adverse events were neutropenia (70.4%), thrombocytopenia (66.7%), and febrile neutropenia (33.3%). In multivariate analysis, early treatment and overall response after chemotherapy were independent favorable prognostic factors for PFS. Overall response after chemotherapy was an independent favorable factor for OS. Among the 8 patients with poor response to zanubrutinib-based treatment, the majority of patients had NOTCH2 mutations (n=8, 100%) and TP53 mutations (n=7, 87.5%). However, these patients achieved an ORR of 75% at 3 months after CD19-CAR-T cell therapy (including 4 cases of complete remission and 2 cases of partial remission). With a median follow-up of 9 months from CAR-T cell infusion (range, 1-16 months), the median PFS was 14.5 months, and the median OS was not reached.ConclusionWith high efficacy and manageable tolerability, zanubrutinib plus salvage chemotherapy may be a potential treatment option for R/R DLBCL. CAR-T cell therapy may be a priority strategy for these poor responders to BTKi-based treatment.

Dataset Information

NEMO-binding domain peptide inhibits constitutive NF-?B activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.

Publications

NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets