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

描述(由申请人提供)：我们的具体目标是识别针对EB病毒(EBV)潜伏感染和EBV相关血液病以及发生在人类宿主中的增殖性疾病的药物。EBV是一种疱疹病毒，感染大约95%的人类人口，通常会导致宿主终身良性的、潜伏的记忆B淋巴细胞感染。然而，EBV是独一无二的，因为潜伏感染可以导致病毒相关的恶性肿瘤，如Burkitt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相关恶性肿瘤的靶向治疗。潜伏膜蛋白2A(LMP2A)是一种在潜伏感染的B淋巴细胞中表达的EBV蛋白，在EBV相关的恶性肿瘤中也可检测到。LMP2A可以改变和模拟由B细胞受体(BCR)诱导的正常B细胞信号通路，以防止细胞凋亡和延长细胞存活。LMP2A的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)，以及Ras/PI3K/Akt通路。我们推测，LMP2A通过改变正常的BCR功能和激活细胞内的促生存和抗凋亡通路来阻断重要的细胞检查点，如Myc诱导的细胞凋亡，从而在EBV潜伏期和EBV相关的发病机制中起关键作用。使用我们实验室建立的一种新的EBV潜伏期体内小鼠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。正如该提案中所描述的，这些抑制剂中的许多目前正在进行测试，并处于治疗其他与EBV相关疾病无关的疾病的人体试验的早期阶段。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，以证明拟议的人类EBV相关淋巴瘤研究的合理性。最后，在我们提出的研究中，可能会确定其他有效靶向LMP2A功能的靶点。总体而言，建议的研究将测试LMP2A信号抑制的可行性，将确定抑制LMP2A信号活性的最有效药物，将为旨在消除EBV潜伏期作为治疗或预防EBV相关恶性肿瘤的体内药物开发研究提供基础，并可能为EBV相关癌症(如EBV相关霍奇金淋巴瘤和非霍奇金淋巴瘤)提供治疗选择。公共卫生相关性：爱泼斯坦-巴尔病毒(EBV)是一种疱疹病毒，它普遍感染人类，通常导致良性的、潜伏的白细胞感染。然而，EBV感染和由此产生的潜伏感染可能导致病毒相关的增殖性疾病，如Burkitt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识别针对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.