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

我们的具体目标是确定针对EB病毒（EBV）潜伏感染和EBV-1的药物。 与人类宿主中发生的血液学癌症和增殖性疾病相关。EB病毒是一种疱疹病毒 这种病毒感染了大约95%的人类，通常会导致良性的潜伏性感染， 记忆B淋巴细胞的宿主的生活。然而，EBV是独特的，因为潜伏感染可导致病毒- 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 (NHL)鼻咽癌（nasopharyngeal carcinoma，NPC）。了解EB病毒潜伏感染提供了深入了解 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- 相关恶性肿瘤。潜伏膜蛋白2A（LMP 2A）是EB病毒潜伏性表达的蛋白质。 感染的B淋巴细胞，并在EBV相关的恶性肿瘤中检测到。LMP 2A改变和模拟正常B细胞 由B细胞受体（BCR）诱导的信号传导途径，以防止细胞凋亡和延长细胞存活。LMP2a 功能依赖于许多细胞蛋白质，包括林恩和Syk蛋白酪氨酸激酶（PTK）， Ras/PI 3 K/Akt通路。我们假设LMP 2A对于EBV潜伏期和EBV相关的免疫应答是必需的。 通过改变正常BCR功能和激活细胞内促存活和抗凋亡的发病机制 阻断重要的细胞检查点的途径，如Myc诱导的细胞凋亡。在体内使用一种新的 在我们的实验室开发的EBV潜伏期小鼠模型和一种新的体外方法，我们将测试 LMP 2A活化蛋白的药理学抑制剂。正如提案中所述，许多这些抑制剂 目前正在进行测试，并处于人体试验的早期阶段，用于治疗与 EBV相关疾病。使用我们的小鼠转基因模型的有希望的数据将为 证明了拟进行的EBV相关淋巴瘤人体研究的合理性。最后，在我们的研究中可能会发现其他目标。 提出了有效靶向LMP 2A功能的研究。总体而言，拟议的研究将测试可行性 的LMP 2A信号传导抑制，将确定最有效的药物抑制LMP 2A信号传导活性，将 为旨在根除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相关的恶性肿瘤提供治疗选择。 相关的癌症，如EBV相关的霍奇金淋巴瘤和NHL。EB病毒（EBV）是一种疱疹病毒，其普遍感染人群，通常导致 白色血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能导致 与病毒相关的增殖性疾病如伯基特S淋巴瘤和霍奇金淋巴瘤。我们的具体 目的是确定靶向EBV潜伏感染和EBV相关淋巴瘤的药物， 通过使用EBV靶向的细胞蛋白的抑制剂来治疗人类宿主。

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.