Discovery of New Treatment Options for EBV-associated Lymphoma and PTLD

发现 EB 病毒相关淋巴瘤和 PTLD 的新治疗方案

• 批准号: 8267730
• 负责人: Richard M Longnecker
• 金额: $ 27.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267730
• 关键词: Adult; Apoptosis; Apoptotic; B-Cell Activation; B-Cell Development; B-Lymphocytes; Benign; Burkitt Lymphoma; Cell Survival; Cells; Clinical Treatment; Data; Development; Disease; Drug Delivery Systems; EBV-associated disease; EBV-associated malignancy; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Lymphoma; Epstein-Barr pathogenesis; Foundations; Gene Expression; Goals; Growth; HIV Infections; Health; Hematologic Neoplasms; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immunosuppression; In Vitro; Individual; Laboratories; Lead; Leukocytes; Life; Lymphocyte; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Membrane Proteins; Memory B-Lymphocyte; Methodology; Methylcellulose; Modeling; Monitor; Mus; Nasopharynx Carcinoma; Non-Hodgkin' s Lymphoma; Organ Transplantation; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Preclinical Drug Evaluation; Prevention; Protein Tyrosine Kinase; Proteins; Receptors, Antigen, B-Cell; Research; Risk; Satellite Viruses; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spleen; Staging; Testing; Therapeutic; Transgenic Mice; Transgenic Model; Viral Proteins; Virus; cellular targeting; human FRAP1 protein; in vivo; infected B cell; inhibitor/antagonist; insight; latent infection; notch protein; novel; prevent; promoter; receptor expression; receptor function; research study; transcription factor; tumor

Our specific goals are to identify drugs that will target Epstein-Barr virus (EBV) latent infections and EBV- associated hematologic cancers and proliferative disorders that occur in the human host. EBV is a herpesvirus that infects approximately 95% of the human population and usually results in the benign, latent infection of memory B lymphocytes for the life of the host. EBV is unique, however, in that latent infection can lead to virus- associated malignancies such as Burkitts lymphoma (BL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). Understanding EBV latent infection provides insight into the pathogenesis of EBV-associated disease and may lead to targeted therapies to prevent or treat EBV- associated malignancies. Latent membrane protein 2A (LMP2A) is an EBV protein expressed in latently infected B-lymphocytes and detected in EBV-associated malignancies. LMP2A alters and mimics normal B cell signaling pathways induced by the B cell receptor (BCR) to prevent apoptosis and prolong cell survival. LMP2A function is dependent on numerous cellular proteins including the Lyn and Syk protein tyrosine kinases (PTKs), and the Ras/PI3K/Akt pathway. We hypothesize that LMP2A is essential for EBV latency and EBV-associated pathogenesis by altering normal BCR function and activating intracellular pro-survival and anti-apoptotic pathways that block important cellular checkpoints such as Myc-induced apoptosis. Using a novel in vivo murine model of EBV latency developed in our laboratory and a novel in vitro methodology, we will test pharmacological inhibitors of LMP2A-activated proteins. As described in the proposal, many of these inhibitors are currently being tested and are in early stages of human trials for treatment of other diseases unrelated to EBV-associated disease. Promising data using our murine transgenic model would provide important data to justify proposed human studies with EBV-related lymphomas. Finally, other targets may be identified in our proposed research that effectively target LMP2A function. Overall, the studies proposed will test the feasibility of LMP2A signaling inhibition, will determine the most effective agents to inhibit LMP2A signaling activity, will provide a foundation for in vivo drug developmental studies aimed at the eradication of EBV latency as treatment or prevention for EBV-associated malignancies, and may offer therapeutic options for EBV- associated cancers such as EBV-associated Hodgkin lymphoma and NHL. Epstein-Barr virus (EBV) is a herpesvirus that ubiquitously infects the human population resulting usually in the benign, latent infection of white blood cells. However, EBV infection and the resulting latent infection can lead to virus-associated proliferative disorders such as Burkitts lymphoma and Hodgkin lymphoma. Our specific goals are to identify drugs that target EBV latent infections and EBV-associated lymphomas that occur in the human host by using inhibitors of cell proteins targeted by EBV.

我们的具体目标是确定针对EB病毒(EBV)潜伏感染和EBV的药物。 发生在人类宿主中的相关血液病和增殖性疾病。EB病毒是疱疹病毒 它感染了大约95%的人类人口，通常会导致良性的潜伏感染 记忆中的B淋巴细胞是宿主的生命。然而，EBV的独特之处在于，潜伏感染可以导致病毒- 相关恶性肿瘤，如Burkitts淋巴瘤(BL)、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤 (非霍奇金淋巴瘤)和鼻咽癌(NPC)。了解EBV潜伏感染有助于深入了解 EBV相关疾病的发病机制，并可能导致靶向治疗以预防或治疗EBV- 相关的恶性肿瘤。潜伏膜蛋白2A(LMP2A)是一种潜伏表达的EBV蛋白。 被感染的B淋巴细胞，并在EBV相关的恶性肿瘤中检测到。LMP2A改变和模拟正常B细胞 由B细胞受体(BCR)诱导的信号通路，以防止细胞凋亡和延长细胞存活。LMP2A 功能依赖于大量的细胞蛋白，包括Lyn和Syk蛋白酪氨酸激酶(PTKs)， Ras/PI3K/Akt途径。我们假设LMP2A对于EBV潜伏期和EBV相关是必不可少的 改变正常BCR功能、激活细胞内促生存和抗凋亡的发病机制 阻断重要细胞检查点的通路，如Myc诱导的细胞凋亡。在体内使用一种新的 我们实验室建立的小鼠EB病毒潜伏期模型和一种新的体外方法学，我们将测试 LMP2A激活蛋白的药理抑制剂。正如提案中所描述的，许多这些抑制剂 目前正在进行测试，并处于治疗其他无关疾病的人体试验的早期阶段 EB病毒相关疾病。使用我们的小鼠转基因模型的有希望的数据将提供重要的数据 证明拟议的人类EBV相关淋巴瘤研究是合理的。最后，可能会在我们的 提出了有效针对LMP2A功能的研究。总括而言，建议的研究将会测试可行性。 对LMP2A信号的抑制，将决定抑制LMP2A信号活性最有效的药物，将 为旨在消除EBV潜伏期的体内药物开发研究提供基础 治疗或预防EBV相关的恶性肿瘤，并可能为EBV- 相关癌症，如EB病毒相关性霍奇金淋巴瘤和非霍奇金淋巴瘤。爱泼斯坦-巴尔病毒(EBV)是一种广泛感染人类的疱疹病毒，通常导致 白血球的良性潜伏感染。然而，EBV感染和由此产生的潜伏感染可能会导致 到病毒相关的增殖性疾病，如Burkitts淋巴瘤和霍奇金淋巴瘤。我们的特定 目标是确定针对EBV潜伏感染和EBV相关淋巴瘤的药物 人类宿主通过使用EBV靶向的细胞蛋白的抑制剂。