A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma

• Published in: PloS one 2014-05, Vol.9 (5), p.e95404
• Main Authors: Habineza Ndikuyeze, Georges, Gaurnier-Hausser, Anita, Patel, Reema, Baldwin, Albert S, May, Michael J, Flood, Patrick, Krick, Erika, Propert, Kathleen J, Mason, Nicola J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Apoptosis; B cells; B-cell lymphoma; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Binding; Biological effects; Biology and Life Sciences; Cancer therapies; Cell proliferation; Chemical properties; Clinical trials; Comparative analysis; Cyclin D; Cytotoxicity; Disease; Dog Diseases - drug therapy; Dog Diseases - metabolism; Dog Diseases - pathology; Dogs; Gene expression; Health aspects; Hematology; Humans; I-kappa B Kinase; Intravenous administration; Kinases; Lymph nodes; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, Large B-Cell, Diffuse - veterinary; Medicine and Health Sciences; Metabolism; Mutation; NF-kappa B - metabolism; NF-κB protein; Non-Hodgkin's lymphomas; Peptides; Peptides - pharmacokinetics; Peptides - pharmacology; Pharmacokinetics; Pharmacology; Protein Structure, Tertiary; Research and Analysis Methods; Sentinel Lymph Node Biopsy; Signal Transduction - drug effects; Signaling; Studies; Tissues; Toxicity; Veterinary colleges; Veterinary medicine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095404

Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of