Inhibiting The Survival And Proliferation Of EBV-Associated Tumor Cells

EBV与许多B细胞和上皮细胞恶性肿瘤相关，包括免疫抑制患者中的B细胞淋巴增生性疾病、伯基特淋巴瘤和鼻咽癌。我们假设，专门针对EBV感染细胞进行破坏的新方法将有助于治疗EBV阳性恶性肿瘤。在这个项目中，我们建议开发三种不同的基于EBV的方法来治疗EBV诱导的肿瘤，利用我们对EBV基因调控和病毒发病机制的广泛知识。在目标1中，我们将抑制潜伏病毒蛋白EBNA 1，以鉴定维持EBV相关淋巴瘤的病毒贡献，从而鉴定特异性抗病毒、抗肿瘤治疗的靶点。在目标2中，我们将研究sirtuins（III型HDAC）在调节病毒潜伏期中的作用，并确定是否可以使用调节sirtuins活性的药物或阻断裂解基因转录负调节因子（ZEB-1）功能的药物来增强裂解诱导策略（由此病毒在肿瘤细胞中从潜伏感染转变为裂解感染形式）。在目标3中，根据我们的 由于HSP-90是一种重要的病毒转化蛋白表达所必需的这一令人兴奋的发现，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抑制剂是否可以在体外特异性地杀死EBV转化的B细胞，并抑制SCID小鼠模型中淋巴组织增生性病变的生长。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开发抗EBV疗法的新靶点的确定，并可能导致通过基于EBV的治疗EBV相关恶性肿瘤的策略合理选择已知药物的确定。

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 EBV-based 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.