Development of a Novel Inducer for EBV Lytic Therapy

 描述（由申请人提供）：EB病毒（EBV）是一种人类疱疹病毒，感染超过90%的世界人口，在各种淋巴和上皮恶性肿瘤（包括伯基特淋巴瘤、鼻咽癌、胃癌、霍奇金淋巴瘤和非霍奇金淋巴瘤）中持续潜伏感染。EBV相关恶性肿瘤的总数估计每年超过200，000例新癌症。EBV在某些肿瘤中几乎普遍存在，这表明可以为这些恶性肿瘤开发新的EBV靶向疗法。目前EBV阳性癌症的化学治疗包括广谱细胞毒性药物，其忽略肿瘤的EBV阳性状态并且具有有限的安全性和选择性。另一种策略，称为溶瘤治疗， 利用刺激潜伏EBV再活化的药物来增强对EBV阳性肿瘤的选择性杀伤，特别是与现有的疱疹病毒裂解性复制抑制剂如更昔洛韦（GCV）组合。目前，包括组蛋白去乙酰化酶（HDAC）抑制剂在内的小分子药物在治疗EBV阳性肿瘤的临床试验中尚未被证明是安全有效的，为了开发新的、更有效的诱导EBV再活化的分子，我们开发了高通量筛选方法来鉴定一类小分子药物，（称为C60系列），其在多种潜伏类型中有效激活EBV裂解周期，包括淋巴母细胞和鼻咽癌细胞系。该提案旨在使用药物化学原理优化这类新鉴定的化学探针，以增强预测体内功效的药物样性质。我们还将开发探针和方法来了解这些EBV裂解激活剂的生化作用机制。最后，我们将使用EBV相关的癌症动物模型来测试先进的探针和先导化合物的体内功效，以更有效地重新激活EBV裂解周期，并且与HDAC抑制剂和佛波酯相比具有显著改善的安全性。中心假设：一种诱导EB病毒阳性肿瘤溶解再激活的小分子将提供一种针对EB病毒阳性恶性细胞的新型治疗方法。化学探针还将提供关于控制EBV潜伏期的机制的新的基本信息。

 DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human herpesvirus that infects over 90% of the world's population that persists as a latent infection in various lymphoid and epithelial malignancies, including Burkitt's lymphomas, nasopharyngeal carcinomas, gastric carcinomas, Hodgkin's and non-Hodgkin's lymphomas. The total number of EBV-associated malignancies is estimated to exceed 200,000 new cancers per year. The near universal presence of EBV in certain tumors suggests that new EBV-targeting therapies could be developed for these malignancies. Current chemotherapeutic treatments of EBV-positive cancers include broad-spectrum cytotoxic drugs that ignore the EBV positive status of tumors and have limited safety and selectivity. An alternative strategy, referred to as oncolytic therapy, utilizes drugs that stimulate reactivation of latent EBV to enhance the selective killing of EBV-positive tumors, especially in combination with existing inhibitors of herpesvirus lytic replicatio, like Ganciclovir (GCV). At present, no small molecule, including histone deacetylase (HDAC) inhibitors, have proven safe or effective in clinical trials for treatment of EBV-positive cancers.In an effort to develop new and more efficacious molecules for inducing EBV reactivation, we have developed high- throughput screening assays to identify a class of small molecules (referred to as the C60 series), that efficiently activate the EBV lytic cycle in multiple latency types, includng lymphoblastoid and nasopharyngeal carcinoma cell lines. This proposal aims to optimize this newly identified class of chemical probe using medicinal chemistry principles to enhance drug-like properties predictive of in vivo efficacy. We will also develop probes and methods to understand the biochemical mechanism of action of these EBV lytic activating agents. Finally, we will use EBV-associated cancer animal models to test the in vivo efficacy of advanced probes and lead compounds to reactivate the EBV lytic cycle more efficiently and with a significantly improved safety profile compared to HDAC inhibitors and phorbol esters. Central Hypothesis: A small molecule that induces lytic reactivation in EBV-positive tumors will provide a novel therapeutic approach to target EBV-positive malignant cells. The chemical probe will also provide new basic information on mechanisms controlling EBV latency.