01232-A: Investigation of NF-kB as a Therapeutic Target in Canine Lymphoma
Grant Status: Closed
Multicentric lymphoma is the most common hematopoietic cancer in dogs and is currently treated using a combination of chemotherapeutic agents, which inhibit cell division and induce cell death. Over the past 30 years, many chemotherapeutic protocols have been used and most induce remission in 65-96% of patients. However, regardless of induction protocol, 85-90% of patients relapse with lethal, drug-resistant lymphoma within 6 to 9 months of diagnosis. In this work we have explored the hypothesis that persistent activation of a major intracellular signaling pathway (the NF-KB pathway) occurs within canine lymphoma cells and that this contributes to lymphoma by driving the expression of genes that drive the tumor to proliferate, resist cell death and develop resistance to chemotherapeutic drugs. The results of this work have revealed that this important intracellular pathway is constitutively active within the tumors of the majority of dogs with the most common subtype of lymphoma, Diffuse Large B Cell Lymphoma (DLBCL). Furthermore, we have shown that the activation of this pathway correlates with increased expression of genes that promote malignant cell proliferation and resistance to chemotherapy. We have traced back the steps of activation of this pathway and have demonstrated that constitutive activity originates at a point in the signaling pathway that is proximal to a protein complex know as IkappaB Kinase (IKK). From this work, we hypothesize that inhibition of this IKK complex represents a novel targeted approach to treat the most common subtype of canine lymphoma. In additional studies we have utilized a selective inhibitor of the NF-KB pathway, known as NBD peptide, to demonstrate that NF-KB inhibition in canine malignant B cells leads to rapid cell death in the laboratory. This preliminary data is being used to support a pilot clinical trial in dogs with relapsed DLBCL to evaluate the safety and efficacy of NBD peptide to inhibit the NF-KB pathway and to enhance clinical response to chemotherapy either at the time of diagnosis and/or during rescue therapy. We hypothesize that the use of a selective inhibitor of the NF-KB pathway will act synergistically with standard chemotherapeutic agents to enhance malignant cell death and improve response rate and remission times in dogs with DLBCL.
Gaurnier-Hausser, A., Patel, R., Baldwin, A. S., May, M. J., & Mason, N. J. (2011). NEMO-Binding Domain Peptide Inhibits Constitutive NF- B Activity and Reduces Tumor Burden in a Canine Model of Relapsed, Refractory Diffuse Large B-Cell Lymphoma. Clinical Cancer Research, 17(14), 4661–4671. https://doi.org/10.1158/1078-0432.CCR-10-3310
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