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

描述（由申请人提供）：NF-？B家族转录因子在调节淋巴细胞增殖、分化和存活中起着核心作用。NF-？B已被确定在许多不同的侵略性淋巴恶性肿瘤在人类和有助于淋巴瘤的发生和化疗耐药性的驱动表达NF-？B靶向促进细胞增殖和抑制细胞凋亡的基因。靶向抑制NF-？B活化代表了治疗淋巴恶性肿瘤的有吸引力的策略。申请组织TheraLogics Inc.有一种含有I的肽抑制剂B激酶抑制序列NF-？B必需调节物（NEMO）结合结构域（NBD）。NBD肽抑制IKKa和IKK？活性，并有效地阻断经典的NEMO依赖性NF-？B激活。在这项建议中，我们将确定是否选择性抑制IKK复合物在体内的NBD肽可以安全地抑制异常，组成NF-？B活性和延长无病生存在私人拥有的狗自发性，复发性NHL。NHL是犬中最常见的造血系统恶性肿瘤，年发病率约为30/100，000只犬。犬NHL与人类NHL具有相似的临床、生物学、行为学、细胞遗传学和基因表达特征，两个物种中显著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，并加速将优化的补救化疗策略转化为犬肿瘤学诊所。此外，我们假设在犬“模型”中观察到的有益效果将与人类癌症治疗直接相关。 公共卫生相关性：NF-家族？B转录因子调节涉及淋巴细胞增殖、分化和存活的过程。在淋巴瘤中，导致这些因子活化的途径是组成性活性的，并促进淋巴瘤发生和化疗耐药性。NEMO结合域肽阻断NF-？体外恶性淋巴细胞中B活化并诱导细胞死亡。本I期STTR的目的是确定使用NBD肽作为化疗的辅助剂是否有益于治疗犬中自发性复发性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，并加速将优化的补救化疗策略转化为犬肿瘤学诊所。此外，我们假设在犬“模型”中观察到的NBD肽的有益作用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.