HSV-Mediated Chemoradiosensitivity Human Glioma Model

HSV介导的化学放射敏感性人类神经胶质瘤模型

• 批准号: 7145786
• 负责人: Constantinos George Hadjipanayis
• 金额: $ 16.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-21 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145786
• 关键词: DNA; DNA repair; apoptosis; birth; brain; chemotherapy; gene therapy; glioma; human; hypoxia; infection; model; mutant; neoplasm /cancer; proteins; xenotransplantation

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.

描述（由申请人提供）：尽管采用积极的多模式治疗，恶性神经胶质瘤患者的中位生存期仍不足 12 个月。放化疗现已成为治疗恶性神经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）与电离辐射 (IR)，然后单独使用 IR。 IR 和化疗效果的增强可能会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）的修复并增强人多形性胶质母细胞瘤（GBM）细胞在辐射后的凋亡。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（10Gy）或TMZ治疗后，小鼠颅内神经胶质瘤模型出现显着的抗肿瘤反应。化疗/放疗激活的基因治疗是一种正在发展的范例，可以对恶性神经胶质瘤进行靶向治疗。我们建议开发和使用新的 HSV 复制缺陷型病毒，其中含有化学诱导型/放射诱导型/缺氧诱导型启动子，可在替莫唑胺、IR 和/或缺氧条件下选择性表达 HSV 立即早期 (IE) 蛋白 ICPO。首先，为了产生新病毒，产生 ICPO 的 HSV 突变体 d106 的天然 ICPO 启动子将被对 IR、TMZ 和/或缺氧响应的启动子取代。其次，HSV突变病毒的最佳体内递送将由CED确定。第三，将利用小鼠神经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专业知识的建议。完成这些目标将有助于 PI 从受指导的临床科学家转变为独立的临床科学家。