NEMO-Binding Domain Peptide Inhibits Constitutive NF-{kappa}B Activity and Reduces Tumor Burden in a Canine Model of Relapsed, Refractory Diffuse Large B-Cell Lymphoma.

摘要

PURPOSE: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-kappaB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-kappaB target genes. Inhibition of the canonical NF-kappaB 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-kappaB activity and to determine the therapeutic relevance of NF-kappaB inhibition in dogs with relapsed, resistant DLBCL. EXPERIMENTAL DESIGN: Canonical NF-kappaB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-kappaB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-kappaB essential modulator-binding domain (NBD) peptide and evaluated for NF-kappaB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-kappaB target gene expression and tumor burden were evaluated pre- and post-treatment. RESULTS: Constitutive canonical NF-kappaB activity and increased NF-kappaB 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-kappaB 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-kappaB 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.