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

描述（由申请人提供）：我们的具体目标是鉴定靶向人类宿主中发生的EB病毒（EBV）潜伏感染和EBV相关血液学癌症和增殖性疾病的药物。EBV是一种疱疹病毒，感染约95%的人群，通常导致记忆B淋巴细胞的良性潜伏感染，持续宿主的一生。然而，EBV是独特的，因为潜伏感染可导致病毒相关的恶性肿瘤，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相关的恶性肿瘤。潜伏膜蛋白2A（LMP 2A）是在潜伏感染的B淋巴细胞中表达并在EBV相关恶性肿瘤中检测到的EBV蛋白。LMP 2A改变并模拟由B细胞受体（BCR）诱导的正常B细胞信号传导途径，以防止细胞凋亡并延长细胞存活。LMP 2A功能依赖于许多细胞蛋白，包括林恩和Syk蛋白酪氨酸激酶（PTK）以及Ras/PI 3 K/Akt途径。我们假设LMP 2A通过改变正常BCR功能和激活细胞内促生存和抗凋亡通路阻断重要的细胞检查点如Myc诱导的凋亡，对EBV潜伏期和EBV相关发病机制至关重要。使用我们实验室开发的一种新的体内EBV潜伏期小鼠模型和一种新的体外方法，我们将测试LMP 2A激活蛋白的药理学抑制剂。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相关疾病无关的其他疾病。使用我们的鼠转基因模型的有希望的数据将提供重要的数据，以证明拟议的人类研究与EBV相关的淋巴瘤。最后，在我们提出的研究中可能会发现其他有效靶向LMP 2A功能的靶标。总体而言，所提出的研究将测试LMP 2A信号传导抑制的可行性，将确定抑制LMP 2A信号传导活性的最有效的药剂，将为旨在根除EBV潜伏期作为EBV相关恶性肿瘤的治疗或预防的体内药物开发研究提供基础，并且可以为EBV相关癌症如EBV相关霍奇金淋巴瘤和NHL提供治疗选择。公共卫生相关性：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导致病毒相关的增殖性疾病，如伯基特淋巴瘤和霍奇金淋巴瘤。我们的具体目标是通过使用EBV靶向细胞蛋白的抑制剂来鉴定靶向EBV潜伏感染和发生在人类宿主中的EBV相关淋巴瘤的药物。

DESCRIPTION (provided by applicant): 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 Burkitt's 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. PUBLIC HEALTH RELEVANCE: 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 Burkitt's lymphoma and Hodgkin lymphoma. Our specific goals are to identify drugs that target EBV latent infections and EBVassociated lymphomas that occur in the human host by using inhibitors of cell proteins targeted by EBV.