title: 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.
abstract: 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 <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.
authors.affiliation: Division of Hematology/Oncology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Georges
authors.initials: G
authors.lastname: Habineza Ndikuyeze
authors.affiliation: Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Gaurnier-Hausser
authors.affiliation: Antech Diagnostics, New Hyde Park, New York, United States of America.
authors.forename: Reema
authors.initials: R
authors.lastname: Patel
authors.affiliation: TheraLogics, Inc., Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.affiliation: 7-020G Katz Centre for Pharmacy and Health Research, The University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Flood
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Krick
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Propert
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D006801:Humans; D051550:I-kappa B Kinase; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021701:Sentinel Lymph Node Biopsy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010455:Peptides; D051550:I-kappa B Kinase