Cancer Therapy: Preclinical NEMO-Binding Domain Peptide Inhibits Constitutive NF-kB 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-kB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-kB target genes. Inhibition of the canonical NF-kB pathway may therefore have therapeutic relevance in ABCDLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-kB activity and to determine the therapeutic relevance of NF-kB inhibition in dogs with relapsed, resistant DLBCL. Experimental Design: Canonical NF-kB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-kB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-kB essential modulator-binding domain (NBD) peptide and evaluated for NF-kB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-kB target gene expression and tumor burden were evaluated preand post-treatment. Results:Constitutive canonical NF-kB activity and increased NF-kB 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-kB 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-kB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABCDLBCL treatment in human patients. Clin Cancer Res; 17(14); 1–11. ’2011 AACR.