EBV lytic re-activation in nasopharyngeal carcinoma

描述（由申请人提供）：鼻咽癌（NPC）是东南亚最常见的癌症之一。虽然鼻咽癌在美国白人人群中的发生率较低，但在移民到美国并居住在南加州的东南亚人中发病率较高。当NPC复发或对初始治疗抵抗时，预后是严峻的，没有有效的治疗方法。鼻咽癌与EB病毒潜伏感染密切相关。潜伏期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，病毒完全表达其约100个基因的基因组，这一过程除了产生新的病毒体之外还导致细胞死亡。因此，潜伏病毒的再活化是杀死感染的肿瘤细胞并增加宿主产生免疫应答的能力的有希望的策略。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。然后，裂解性胸苷激酶和磷酸转移酶基因的新表达可以允许更昔洛韦的肿瘤特异性磷酸化/活化，抑制病毒和细胞DNA复制和细胞死亡。因此，硼替佐米对裂解复制的再激活具有通过以下几种机制杀死肿瘤细胞的潜力：1）硼替佐米诱导的细胞凋亡; 2）由于病毒复制导致的死亡; 3）诱导抗EBV免疫应答; 4）同时施用更昔洛韦对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重新激活可能导致高级别的病毒血症。因此，该I期/可行性临床试验将测试硼替佐米和更昔洛韦联合治疗复发性NPC患者的安全性，特别是询问感染是否可以控制以及是否可以确定EBV的裂解性再活化。如果成功，它将为更大规模的II期研究奠定基础，以更准确地检查抗肿瘤疗效。

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.