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将针对Epstein-Barr病毒（EBV）潜在感染和EBV-的药物 相关的血液学癌症和人类宿主中发生的增殖疾病。 EBV是疱疹病毒 这感染了大约95％的人口，通常会导致良性的潜在感染 记忆B淋巴细胞为宿主的寿命。但是，EBV是独一无二的，因为潜在感染会导致病毒 - 相关的恶性肿瘤，例如伯基特淋巴瘤（BL），霍奇金淋巴瘤（HL），非霍奇金淋巴瘤 （NHL）和鼻咽癌（NPC）。了解EBV潜在感染提供了有关 EBV相关疾病的发病机理，可能导致靶向疗法预防或治疗EBV- 相关的恶性肿瘤。潜在的膜蛋白2a（LMP2A）是在潜在的EBV蛋白 被感染的B淋巴细胞，并在与EBV相关的恶性肿瘤中检测到。 LMP2A改变并模仿正常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 功能取决于许多细胞蛋白，包括Lyn和Syk蛋白酪氨酸激酶（PTK）， 以及RAS/PI3K/AKT途径。我们假设LMP2A对于EBV延迟和EBV相关至关重要 通过改变正常的BCR功能并激活细胞内促生存和抗凋亡，发病机理 阻止重要的细胞检查点（例如MYC诱导的凋亡）的途径。使用小说在体内 EBV潜伏期的鼠模型在我们的实验室和一种新颖的体外方法中，我们将测试 LMP2A激活蛋白的药理抑制剂。如提案中所述，许多这些抑制剂 目前正在接受测试，并处于人类试验的早期阶段，以治疗其他与之无关的疾病 与EBV相关的疾病。使用我们的鼠转基因模型的有希望的数据将为 通过与EBV相关的淋巴瘤进行了拟议的人类研究。最后，可以在我们的 提出的有效针对LMP2A功能的研究。总体而言，提出的研究将测试可行性 LMP2A信号抑制的抑制作用将确定抑制LMP2A信号活性的最有效的药物 为旨在消除EBV潜伏期的体内药物发育研究提供了基础 治疗或预防与EBV相关的恶性肿瘤，并可能为EBV提供治疗选择 相关的癌症，例如与EBV相关的霍奇金淋巴瘤和NHL。爱泼斯坦 - 巴尔病毒（EBV）是一种普遍感染的人口的疱疹病毒 良性，白细胞的潜在感染。但是，EBV感染和由此产生的潜在感染可以引导 与病毒相关的增生性疾病，例如伯基特的淋巴瘤和霍奇金淋巴瘤。我们的具体 目标是确定针对EBV潜在感染和与EBV相关的淋巴瘤的药物 通过使用由EBV靶向的细胞蛋白抑制剂的宿主。