Inhibiting The Survival And Proliferation Of EBV-Associated Tumor Cells

EB病毒与许多B细胞和上皮细胞恶性肿瘤有关，包括B细胞淋巴增生性 免疫抑制患者的疾病、伯基特淋巴瘤和鼻咽癌。我们 假设特异性靶向EBV感染细胞进行破坏的新方法将有助于 EBV阳性恶性肿瘤的治疗。在这个项目中，我们建议开发三种不同的基于EBV的 治疗EBV诱导的肿瘤的方法，利用我们广泛的知识， EB病毒基因调控与病毒发病机制在目标1中，我们将抑制潜伏病毒蛋白EBNA 1， 鉴定维持EBV相关淋巴瘤的病毒贡献，从而鉴定特异性靶点， 抗病毒、抗肿瘤治疗。在目标2中，我们将研究sirtuins（III型HDAC）在调节 病毒潜伏期，并确定是否有裂解诱导策略（由此病毒从潜伏期转换为 肿瘤细胞中感染的裂解形式）可以使用调节沉默调节蛋白活性的试剂或 阻断裂解基因转录负调节因子（ZEB-1）的功能。在目标3中，根据我们的 令人兴奋的发现是HSP-90是表达一种重要的病毒转化蛋白所必需的，我们将 研究HSP-90在病毒发病机制中的重要性，并确定新开发的HSP-90抑制剂是否 可在体外特异性杀伤EBV转化的B细胞，并抑制淋巴增殖性淋巴细胞的生长， SCID小鼠模型中的病变。我们还将确定HSP-90抑制剂是否可用于阻断 病毒复制的裂解形式。我们提出的研究将导致确定新的目标， 抗EBV治疗，并可能导致识别已知的药物合理选择的EBV为基础的战略 用于治疗EBV相关的恶性肿瘤。

EBV is associated with a number of B cell and epithelial cell malignancies, including B-cell lymphoproliferative disease in immunosuppressed patients, Burkitt lymphomas, and nasopharyngeal carcinomas. We hypothesize that new approaches that specifically target EBV-infected cells for destruction will be useful for the treatment of EBV-positive malignancies. In this project, we propose to develop three different EBVbased approaches for the treatment of EBV-induced tumors, capitalizing upon our extensive knowledge of EBV gene regulation and viral pathogenesis. In aim 1, we will inhibit the latent viral protein, EBNA1, to identify viral contributions that sustain EBV-associated lymphomas and thereby identify targets for specific anti-viral, anti-tumor therapies. In aim 2, we will examine the role of sirtuins (type III HDACs) in regulating viral latency, and determine if strategies for lytic-induction (whereby the virus is switched from the latent to lytic form of infection in tumor cells) can be enhanced using agents which regulate sirtuin activity, or agents that block the function of a negative regulator of lytic gene transcription (ZEB-1). In aim 3, based upon our exciting finding that HSP-90 is required for expression of an essential viral transforming protein, we will examine the importance of HSP-90 in viral pathogenesis and determine if newly developed HSP-90 inhibitors can be used specifically to kill EBV-transformed B cells in vitro and inhibit the growth of lymphoproliferative lesions in SCID mouse models. We will also determine if HSP-90 inhibitors can be used to block the lytic form of viral replication. Our proposed studies will lead to the identification of new targets for developing anti-EBV therapies and may lead to the identification of known drugs rationally chosen by EBV-based strategies for treating EBV-associated malignancies.