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细胞淋巴增生性疾病 免疫抑制患者的疾病、Burkitt淋巴瘤和鼻咽癌。我们 假设专门针对EBV感染细胞进行破坏的新方法将对 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 EBV诱导的肿瘤的治疗方法，利用我们对 EBV基因调控与病毒致病机制。在目标1中，我们将抑制潜伏的病毒蛋白EBNA1，以 确定维持EBV相关淋巴瘤的病毒贡献，从而确定特定的靶点 抗病毒、抗肿瘤疗法。在目标2中，我们将研究sirtuins(III型HDAC)在调节 病毒潜伏期，并确定裂解诱导策略(病毒从潜伏期切换到 可使用调节sirtuin活性的试剂或试剂来增强 这阻断了裂解基因转录的负调控因子(Zeb-1)的功能。在目标3中，基于我们的 令人兴奋的发现，HSP-90是表达一种重要的病毒转化蛋白所必需的，我们将 检查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 可在体外特异性杀伤EBV转化的B细胞并抑制淋巴组织增殖性细胞的生长 SCID小鼠模型的损伤。我们还将确定是否可以使用HSP-90抑制剂来阻断 病毒复制的裂解形式。我们建议的研究将导致确定新的发展目标。 抗EBV疗法，并可能导致通过基于EBV的策略合理选择已知药物的识别 用于治疗EB病毒相关的恶性肿瘤。

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.