Research Project
8006050
DESCRIPTION (provided by applicant): The NF-?B family of transcription factors plays a central role in the regulation of lymphocyte proliferation, differentiation and survival. Aberrant constitutive activation of NF-?B has been identified in many different aggressive lymphoid malignancies in humans and contributes to lymphomagenesis and chemotherapeutic resistance by driving the expression of NF-?B target genes that promote cellular proliferation and inhibit cellular apoptosis. Targeted inhibition of NF-?B activation represents an attractive strategy for the treatment of lymphoid malignancies. The applicant organization, TheraLogics Inc., has a peptide inhibitor containing an I?B kinase inhibitory sequence NF-?B essential modulator (NEMO) binding domain (NBD). NBD peptide inhibits both IKKa and IKK[unreadable] activity and efficiently blocks classical, NEMO dependent NF-?B activation. In this proposal we will determine whether selective inhibition of the IKK complex in vivo by NBD peptide can safely inhibit aberrant, constitutive NF-?B activity and prolong disease free survival in privately owned dogs with spontaneous, relapsed NHL. NHL is the most common hematopoetic malignancy in the dog, with an annual incidence of ~30/100,000 dogs. Canine NHL shares similar clinical, biological, behavioral, cytogenetic and gene expression characteristics to NHL in humans and significant morbidity and mortality is associated with drug-resistant disease in both species. The purpose of this phase I STTR is to determine whether the use of NBD peptide as an adjunct agent to cytotoxic chemotherapy is beneficial in the treatment of relapsed NHL in dogs. Our goal is to understand the potential of this agent to enhance apoptotic cell death in malignant lymphocytes and accelerate the translation of an optimized rescue chemotherapeutic strategy into the canine oncology clinics. Furthermore we hypothesize that beneficial effects seen in the canine "model" will have direct translational relevance to human cancer therapeutics. PUBLIC HEALTH RELEVANCE: The family of NF-?B transcription factors regulates processes involved in lymphocyte proliferation, differentiation and survival. In lymphoma, the pathways that lead to activation of these factors are constitutively active and promote lymphomagenesis and chemotherapy resistance. NEMO-binding domain peptide blocks NF-?B activation and induces cell death in malignant lymphocytes in vitro. The purpose of this phase I STTR is to determine whether the use of NBD peptide as an adjunct agent to chemotherapy is beneficial in the treatment of spontaneous, relapsed NHL in dogs. Our goal is to understand the potential of this agent to enhance apoptotic cell death in malignant lymphocytes and accelerate the translation of an optimized rescue chemotherapeutic strategy into the canine oncology clinics. Furthermore we hypothesize that beneficial effects of NBD peptide seen in the canine "model" will have direct translational relevance to human cancer therapeutics.
