HSV-Mediated Chemoradiosensitivity Human Glioma Model

描述（由申请人提供）：尽管进行了积极的多模式治疗，恶性胶质瘤患者的中位生存期仍低于12个月。放化疗现在是治疗恶性胶质瘤的标准治疗方法，包括同时使用替莫唑胺（TMZ）（一种口服DNA烷化剂）和电离辐射（IR），然后单独使用IR。增强IR和化疗的效果可进一步提高患者的生存率和生活质量。我们已经证明，单纯疱疹病毒（HSV）蛋白，ICPO，可以抑制DNA双链断裂（DSB）的修复，并增强照射后的人多形性胶质母细胞瘤（GBM）细胞的凋亡。此外，我们有初步的数据显示，在小鼠颅内胶质瘤模型后，脑内对流增强递送（CED）的ICPO产生HSV-1突变体，d106，与全脑照射（10戈伊）或TMZ治疗相结合的显着的抗肿瘤反应。化疗/放疗激活的基因治疗是一种发展中的范例，可以允许恶性胶质瘤的靶向治疗。我们建议开发和使用新的HSV复制缺陷型病毒，该病毒含有化学诱导/放射诱导/低氧诱导启动子，该启动子在替莫唑胺、IR和/或低氧条件下选择性表达HSV立即早期（IE）蛋白ICPO。首先，为了产生新的病毒，产生ICPO的HSV突变体d106的天然ICPO启动子将被响应IR、TMZ和/或缺氧的启动子取代。第二，HSV突变病毒的最佳递送将通过CED在体内确定。第三，通过IR、TMZ和缺氧在体外和体内用小鼠胶质瘤模型评估ICPO的转录靶向。还提出了发展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的建议。这些目标的完成将有助于PI从指导临床科学家转变为独立临床科学家。

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.