HSV-Mediated Chemoradiosensitivity Human Glioma Model

描述（由申请人提供）：尽管积极的多模式治疗，恶性胶质瘤患者的中位生存期仍少于12个月。放化疗目前是恶性胶质瘤治疗的标准治疗方法，包括同时使用替莫唑胺（TMZ），一种口服DNA烷基化剂，与电离辐射（IR）一起使用，然后单独使用IR。IR和化疗效果的增强可进一步提高患者的生存和生活质量。我们发现单纯疱疹病毒（HSV）蛋白ICPO可以抑制DNA双链断裂（DSBs）的修复，并促进人多形性胶质母细胞瘤（GBM）细胞在辐照后的凋亡。此外，我们的初步数据显示，在脑内对流增强递送（CED）产生icpo的HSV-1突变体d106，结合全脑照射（10 Gy）或TMZ治疗后，在小鼠颅内胶质瘤模型中有显著的抗肿瘤反应。化疗/放疗激活基因治疗是一种发展模式，可以允许靶向治疗恶性胶质瘤。我们建议开发和使用新的HSV复制缺陷病毒，这些病毒含有化学诱导/放射性诱导/低氧诱导启动子，在temozolomide、IR和/或缺氧条件下选择性表达HSV即时早期（IE）蛋白ICPO。首先，为了产生新病毒，将产生ICPO的HSV突变体d106的原生ICPO启动子替换为对IR、TMZ和/或缺氧有反应的启动子。其次，通过CED在体内确定HSV突变病毒的最佳递送。第三，通过小鼠胶质瘤模型，在体外和体内评估IR、TMZ和缺氧对ICPO的转录靶向作用。还提出了Pi在分子生物学，癌症生物学，病毒基因治疗和人类癌症建模领域的专业知识发展的建议。这些目标的完成将有助于PI从一个有指导的过渡到独立的临床医生科学家。

DESCRIPTION (provided by applicant): The median survival for patients with malignant glioma remains less than 12 months despite aggressive multimodal therapy. Chemoradiation is now a standard of care in the treatment of malignant gliomas involving the use of concurrent temozolomide (TMZ), an oral DNA alkylating agent, with ionizing radiation (IR) followed by IR alone. Enhancement of the effects of IR and chemotherapy may further increase patient survival and quality of life. We have shown that the herpes simplex virus (HSV) protein, ICPO, can inhibit the repair of DNA double-strand breaks (DSBs) and enhance apoptosis of human glioblastoma multiforme (GBM) cells after irradiation. In addition, we have preliminary data showing a significant antitumor response in a mouse intracranial glioma model after intracerebral convection-enhanced delivery (CED) of the ICPO-producing HSV-1 mutant, d106, in combination with whole-brain irradiation (10 Gy) or TMZ treatment. Chemo/radiotherapy-activated gene therapy is a developing paradigm that that can allow for targeted treatment of malignant gliomas. We propose the development and use of new HSV replication-defective viruses that contain chemoinducible/radioinducible/hypoxiainducible promoters that selectively express the HSV immediate-early (IE) protein, ICPO, with temozolomide, IR, and/or hypoxic conditions. First, to produce the new viruses, the native ICPO promoter of the ICPO-producing HSV mutant, d106, will be substituted with promoters responsive to IR, TMZ, and/or hypoxia. Second, optimal delivery of HSV mutant viruses will be determined in vivo by CED. Third, transcriptional targeting of ICPO by IR, TMZ, and hypoxia will be assessed in vitro and in vivo with a mouse glioma model. A proposal for the development of the Pi's expertise in the fields of molecular biology, cancer biology, viral gene therapy, and human cancer modeling is also presented. Completion of these goals will serve to transition the PI from a mentored to independent clinician scientist.