报告题目：Targeting Malignant Brain Tumors with Oncolytic Picornavirus SVV-001: an in vivo Study in Patient Derived Orthotopic Xenograft (PDOX) Mouse Models

报 告 人：Xiao-Nan Li, M.D., Ph.D，Baylor College of Medicine

报告时间：2015年10月16日（周五） 上午　 10:30

报告地点：嘉定园区学术活动中心多功能厅

报告人简介：

李晓楠博士，现任美国德克萨斯州贝勒医学院儿科系associate professor。德州儿童医院德州儿童癌症研究中心分子神经肿瘤研究室主任。主要研究方向为小儿神经肿瘤。1985年李教授毕业于苏州医学院放射医学系；1993年获得苏州医学院神经外科医学博士学位；1996至2001年赴美国贝勒医学院从事博士后研究。曾于1997年因脑肿瘤诱导分化研究获得世界青年神经外科医师大奖。李教授建立了世界上第一个系列的人类来源的脑肿瘤的原位移植瘤动物模型（Patient derived orthotopic xenograft mouse model, PDOX also known as PDX）。这一系列是目前世界上最大最全的小儿神经肿瘤模型库。涵盖了几乎所有恶性的小儿脑肿瘤类型，模型总数已经超过八十余个。目前李教授课题组利用这一独特的生物资源进行了多方向的生物学和临床前药物研究。特别对肿瘤转移，侵润和肿瘤干细胞的发生发展进行了深入探讨。李教授的研究有十二项，总额超过一千万美元的资金支持。其中李教授作为课题负责人领导了五项总额为五百万美元以上的NIH　R01，U01以及德州癌症预防与癌症研究院（CPRIT）的重大项目。目前担任NCI下属小儿脑肿瘤研究计划中高度恶性胶质瘤委员会主席；生物委员会和髓母细胞瘤委员会委员；脑干胶质瘤委员会委员。李教授同时担任NIH/NCI儿童临床前研究计划执行委员会委员。李教授为近二十个杂志审稿人，已经发表国际论文六十余篇。

报告简介：

Brain tumors are the leading cause of cancer related death in children. Difficulties of drug delivery across the blood brain barrier (BBB) and failure to eliminate cancer stem cells are believed to be the major causes of tumor recurrences in malignant brain tumors.　Seneca Valley virus-001 (SVV-001) is a naturally occurring and replication competent oncolytic Picornavirus that can be systemically administered. Here, we report its anti-tumor activities against a large pane of PDOX models, including medulloblastoma (n=10), glioblastoma (GBM) (n=6), CNS PNET (n=1), diffuse intrinsic pontine glioma (DIPG) (n=4). These models were shown to have replicated the histopathological features, invasive/metastatic phenotypes, and genetic abnormalities of the original patient tumors and have also maintained cancer stem cell pool during serial subtransplantations in mouse brains.　We found that SVV-001 at (0.001-25 viral particle/cell) killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing cancer stem cell surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in approximately 50% of the models tested, i.e. 5 /10 medulloblastomas, 4/6 GBMs, 1/1 CNS PNET, and 2/4 DIPGs. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 (9 x 1012 viral particle/kg) in the permissive PDOX models led to widespread infection and killing of the pre-formed PDOX tumors,　resulting in significant increase of survival times in 2/2 medulloblastoma, 4/6 GBM, 1/1 CNS PNET and 2/4 DIPG models.　In the two medulloblastoma models (group 3 and group 4), complete elimination of intra-cerebellar xenografts was confirmed in 8 of the 10 long-term survivors. Normal mouse brain cells were not affected. Mechanistically, we found that the intracellular replication of SVV-001 is mediated through a subverted autophagy that is different from the bona fide autophagic process induced by rapamycin in medulloblastoma, and the binding of SVV-001 to GBM cells was mediated by α2,3-linked and　α2,6-linked sialic acid. Our data suggest that SVV-001 is well suited for brain tumor treatment, and they expand current views in the oncolytic therapy field regarding the utility of oncolytic viruses in simultaneous targeting of stem and non-stem tumor cells.