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

Purpose: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-kappa B activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-kappa B target genes. Inhibition of the canonical NF-kappa 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-kappa B activity and to determine the therapeutic relevance of NF-kappa B inhibition in dogs with relapsed, resistant DLBCL. Experimental Design: Canonical NF-kappa B activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-kappa 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-kappa B essential modulator-binding domain (NBD) peptide and evaluated for NF-kappa B activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-kappa B target gene expression and tumor burden were evaluated pre- and post-treatment. Results: Constitutive canonical NF-kappa B activity and increased NF-kappa 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-kappa B target gene expression and reduced tumor burden. Conclusions: 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-kappa B inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients. Clin Cancer Res; 17(14); 4661-71. (C)2011 AACR.