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Journal article
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
PloS one, v 9(5), pp e95404-e95404
2014
PMID: 24798348
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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- 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
- Creators
- Georges Habineza Ndikuyeze - Division of Hematology/Oncology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaAnita Gaurnier-Hausser - Drexel UniversityReema Patel - Antech Diagnostics, New Hyde Park, New York, United States of AmericaAlbert S Baldwin - University of North Carolina at Chapel HillMichael J May - University of PennsylvaniaPatrick Flood - University of AlbertaErika Krick - University of PennsylvaniaKathleen J Propert - University of PennsylvaniaNicola J Mason - University of Pennsylvania
- Publication Details
- PloS one, v 9(5), pp e95404-e95404
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- R41 AI088870 / NIAID NIH HHS 1R41AI088870-01A1 / NIAID NIH HHS R01 HL096642 / NHLBI NIH HHS UC2 CA148149 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Intensive Medical Sciences (IMS)
- Web of Science ID
- WOS:000336656000018
- Scopus ID
- 2-s2.0-84900420238
- Other Identifier
- 991019302021304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology