HSV-Mediated Chemoradiosensitivity Human Glioma Model

描述(由申请人提供)：恶性胶质瘤患者的中位生存期仍然不到12个月，尽管进行了积极的多模式治疗。化疗现在是治疗恶性胶质瘤的标准治疗方法，包括同时使用口服DNA烷化剂替莫唑胺(TMZ)和电离辐射(IR)，然后再单独使用IR。增强IR和化疗的效果可能会进一步提高患者的存活率和生活质量。我们发现单纯疱疹病毒(HSV)蛋白ICPO能抑制照射后人多形性胶质母细胞瘤(GBM)细胞DNA双链断裂的修复，促进细胞的凋亡。此外，我们的初步数据显示，在小鼠脑内对流增强递送(CED)产生ICPO的HSV-1突变体d106后，结合全脑照射(10GY)或TMZ治疗，在小鼠脑内胶质瘤模型中有显著的抗肿瘤反应。化疗/放疗激活的基因治疗是一种发展中的范例，可以对恶性胶质瘤进行靶向治疗。我们建议开发和使用含有chemoinducible/radioinducible/hypoxiainducible启动子的新的单纯疱疹病毒复制缺陷病毒，该病毒在替莫唑胺、IR和/或低氧条件下选择性地表达单纯疱疹病毒即刻早期(IE)蛋白。首先，为了产生新病毒，产生ICPO的HSV突变体d106的天然ICPO启动子将被IR、TMZ和/或缺氧反应的启动子取代。其次，CED将在体内确定HSV突变病毒的最佳输送方式。第三，将在体外和体内用小鼠脑胶质瘤模型评估IR、TMZ和低氧对ICPO的转录靶向性。还提出了发展国际癌症研究所在分子生物学、癌症生物学、病毒基因治疗和人类癌症模型领域的专业知识的建议。完成这些目标将有助于将PI从一名指导的临床科学家转变为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.