EBV lytic re-activation in nasopharyngeal carcinoma

描述（申请人提供）：鼻咽癌（NPC）是东南亚最常见的癌症之一。虽然鼻咽癌在美国高加索人群中的发病率较低，但在移民到美国并居住在南加州的东南亚人群中发病率很高。当鼻咽癌复发或对初始治疗有耐药性时，预后很糟糕，没有有效的治疗方法。鼻咽癌与eb病毒（EBV）潜伏感染密切相关。潜伏期间有限的病毒基因表达允许EBV逃避免疫识别。然而，在裂解复制阶段，病毒完全表达其大约100个基因的基因组，这一过程除了产生新的病毒粒子外，还会导致细胞死亡。因此，重新激活潜伏病毒是一种很有希望的策略，可以杀死被感染的肿瘤细胞并增加宿主的免疫反应能力。我们的数据显示，蛋白酶体抑制剂硼替佐米可以高效地从潜伏感染的细胞系中重新激活EBV。裂解胸苷激酶和磷酸转移酶基因的新表达允许肿瘤特异性磷酸化/激活更昔洛韦，抑制病毒和细胞DNA复制和细胞死亡。因此，硼替佐米重新激活裂解复制可能通过以下几种机制杀死肿瘤细胞：1)硼替佐米诱导细胞凋亡；2)病毒复制导致死亡；3)诱导抗ebv免疫反应；4)同时给予更昔洛韦对DNA的影响。然而，尽管理论上可以用更昔洛韦控制，但在免疫抑制的癌症患者中，病毒复制的再激活可能导致高级别病毒血症。因此，这项I期/可行性临床试验将测试硼替佐米和更昔洛韦联合用于复发性鼻咽癌患者的安全性，特别是询问是否可以控制感染以及是否可以识别EBV的溶解性再激活。如果成功，它将为更大规模的II期研究奠定基础，以更准确地检测抗肿瘤疗效。

DESCRIPTION (provided by applicant): Nasopharyngeal carcinoma (NPC) is one of the most common cancers in Southeast Asia. Although the frequency of NPC in the American Caucasian population is low, the incidence is high among Southeast Asian individuals who immigrate to the US and reside in Southern California. When NPC recurs or is resistant to initial therapy, the prognosis is grim with no effective treatment available. NPC is closely associated with latent infection by Epstein-Barr virus (EBV). The limited viral gene expression during latency allows EBV to evade immune recognition. However, during the lytic replication phase, the virus fully expresses its genome of approximately 100 genes, a process that leads to cell death in addition to the production of new virions. Therefore, reactivation of the latent virus is a promising strategy to kill the infected tumor cell and increase the host's ability to mount immune responses. Our data show the proteasome inhibitor bortezomib can reactivate EBV from latently infected cell lines with high efficiency. Neo-expression of the lytic thymidine kinase and phosphotransferase genes can then allow tumor-specific phosphorylation/activation of gancyclovir with inhibition of viral and cellular DNA replication and cell death. Thus, re-activation of lytic replication by bortezomib has the potential for killing tumor cells by several mechanisms: 1) Bortezomib-induced apoptosis; 2) death due to viral replication; 3) Induction of anti-EBV immune responses; 4) effects on DNA by concurrently administered gancyclovir. However, although theoretically controlled with gancyclovir, re-activation of viral replication in immunosuppressed patients with cancer could lead to high grade viremia. Thus, this phase I/feasibility clinical trial will test the safety of combining bortezomib and gancyclovir in patients with recurrent NPC, specifically asking whether infection can be controlled and if lytic reactivation of EBV can be identified. If successful, it would form the basis for larger phase II studies to more accurately examine anti-tumor efficacy.