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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
Journal article   Peer reviewed

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

Anita Gaurnier-Hausser, Reema Patel, Albert S Baldwin, Michael J May and Nicola J Mason
Clinical cancer research, v 17(14), pp 4661-4671
15 Jul 2011
DOI: https://doi.org/10.1158/1078-0432.CCR-10-3310
PMID: 21610150
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/1078-0432.CCR-10-3310View
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Abstract

Animals Apoptosis - drug effects Apoptosis - genetics Cell Line, Tumor Disease Models, Animal Dogs Gene Expression Regulation, Neoplastic - drug effects Humans I-kappa B Kinase - metabolism Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology NF-kappa B - antagonists & inhibitors NF-kappa B - metabolism Peptides - metabolism Peptides - pharmacology Peptides - therapeutic use Pilot Projects Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Recurrence Tumor Burden - drug effects Up-Regulation - genetics
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 constitutive NF-κB activity and to determine the therapeutic relevance of NF-κB inhibition in dogs with relapsed, resistant DLBCL. Canonical NF-κB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-κB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-κB essential modulator-binding domain (NBD) peptide and evaluated for NF-κB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-κB target gene expression and tumor burden were evaluated pre- and post-treatment. Constitutive canonical NF-κB activity and increased NF-κB 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-κB 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-κB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients.

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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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