Evaluation of NBD Peptides as an Adjunct Therapy for the Treatment of Non-Hodgkin

描述（由申请人提供）：NF-？B家族转录因子在淋巴细胞增殖、分化和存活的调控中起着核心作用。NF-?的异常构型激活B已在人类许多不同的侵袭性淋巴细胞恶性肿瘤中被发现，并通过驱动NF-?的表达促进淋巴瘤的发生和化疗耐药。B促进细胞增殖和抑制细胞凋亡的靶基因。靶向抑制NF-？B活化是治疗淋巴细胞恶性肿瘤的一个有吸引力的策略。申请机构TheraLogics Inc.有一种含有I？B激酶抑制序列NF-？B基调制（NEMO）结合域（NBD）。NBD肽抑制IKKa和IKK¿活性并有效阻断经典的NEMO依赖性NF-？B激活。在本研究中，我们将确定NBD肽在体内选择性抑制IKK复合物是否可以安全地抑制异常的、构成性NF-？B活性和延长私人养犬自发性复发性NHL的无病生存期。NHL是犬中最常见的造血恶性肿瘤，年发病率约为30/100,000。犬类NHL与人类NHL具有相似的临床、生物学、行为、细胞遗传学和基因表达特征，两者的发病率和死亡率均与耐药疾病相关。本I期STTR的目的是确定使用NBD肽作为细胞毒性化疗的辅助剂是否有益于治疗犬复发性NHL。我们的目标是了解这种药物在恶性淋巴细胞中增强凋亡细胞死亡的潜力，并加速将优化的拯救化疗策略转化为犬肿瘤临床。此外，我们假设在犬类“模型”中看到的有益效果将与人类癌症治疗具有直接的翻译相关性。

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¿ 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.