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: 8245223
• 负责人: Richard M Longnecker
• 金额: $ 7.96万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245223
• 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 Epstein-Barr 病毒 (EBV) 潜伏感染和 EBV- 的药物 人类宿主中发生的相关血液癌症和增殖性疾病。 EBV是一种疱疹病毒 感染约 95% 的人口，通常会导致良性潜伏感染 B淋巴细胞对宿主的一生都有记忆。然而，EB 病毒的独特之处在于，潜伏感染可能导致病毒- 相关恶性肿瘤，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，并可能导致预防或治疗 EBV 的靶向治疗 相关恶性肿瘤。潜伏膜蛋白 2A (LMP2A) 是一种潜伏表达的 EBV 蛋白。 感染的 B 淋巴细胞并在 EBV 相关恶性肿瘤中检测到。 LMP2A 改变并模仿正常 B 细胞 B 细胞受体 (BCR) 诱导的信号通路可防止细胞凋亡并延长细胞存活。 LMP2A 功能依赖于许多细胞蛋白，包括 Lyn 和 Syk 蛋白酪氨酸激酶 (PTK)， 和 Ras/PI3K/Akt 通路。我们假设 LMP2A 对于 EBV 潜伏期和 EBV 相关性至关重要 通过改变正常的 BCR 功能并激活细胞内的促生存和抗凋亡来发挥发病机制 阻断重要细胞检查点（例如 Myc 诱导的细胞凋亡）的途径。使用小说体内 我们实验室开发的 EBV 潜伏期小鼠模型和一种新颖的体外方法，我们将测试 LMP2A 激活蛋白的药理学抑制剂。正如提案中所述，许多抑制剂 目前正在接受测试，并处于人体试验的早期阶段，用于治疗与此无关的其他疾病 EBV 相关疾病。使用我们的小鼠转基因模型获得的有希望的数据将为 证明拟议的 EB 病毒相关淋巴瘤人体研究的合理性。最后，我们可以确定其他目标 提出了有效针对 LMP2A 功能的研究。总体而言，拟议的研究将测试可行性 LMP2A 信号传导抑制的研究将确定抑制 LMP2A 信号传导活性的最有效药物， 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 相关恶性肿瘤，并可能为 EBV 提供治疗选择 相关癌症，例如 EBV 相关霍奇金淋巴瘤和 NHL。 EB 病毒 (EBV) 是一种疱疹病毒，普遍感染人类，通常会导致 白细胞的良性潜伏感染。然而，EBV 感染和由此产生的潜伏感染可导致 与病毒相关的增殖性疾病，例如伯基特淋巴瘤和霍奇金淋巴瘤。我们的具体 目标是确定针对 EBV 潜伏感染和 EBV 相关淋巴瘤的药物 通过使用 EBV 靶向的细胞蛋白抑制剂来对抗人类宿主。