Genetically-Modified Neural Stem Cell Based Virotherapy for Invasive Gliomas

基于基因修饰的神经干细胞的病毒疗法治疗侵袭性胶质瘤

• 批准号: 8725602
• 负责人: Atique U. Ahmed
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725602
• 关键词: Address; Adenoviruses; Antineoplastic Agents; Blood Vessels; Brain; Cancer Prognosis; Cell Line; Cell Therapy; Cell Transplants; Cells; Clinic; Clinical Trials; Cotton Rats; Cues; Cytolysis; Data; Development; Disease; Engineering; Exhibits; FDA approved; Future; Genetic; Glioblastoma; Glioma; Home environment; Homing; Human; Human Adenoviruses; Imagery; Immune response; Immune system; Immunocompetent; Immunosuppressive Agents; Infection; Investigation; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Modification; Molecular; Nature; Neoplasm Metastasis; Neuraxis; Oncolytic; Oncolytic viruses; Patients; Pattern; Play; Property; Protocols documentation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Stem cells; Survival Rate; System; Therapeutic; Time; Treatment Efficacy; Tropism; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Viral; Virotherapy; Virus; Virus Diseases; Virus Replication; anti-cancer therapeutic; base; cell type; design; drug development; immune activation; improved; in vivo; neoplastic cell; nerve stem cell; nestin protein; neuro-oncology; novel; novel therapeutic intervention; pre-clinical; stem cell niche; targeted delivery; tumor

Project Summary: Glioblastoma multiforme is a primary malignancy of the central nervous system that is nearly universally fatal due to the disseminated nature of these tumors. In this context, our lab and others have investigated unique tumor-tropic properties of neural stem cells (NSCs) as a novel platform for targeted delivery of anti-cancer agents in the brain. However, despite the strong tumor tropism exhibited by NSCs, only a small portion of the transplanted cells is able to migrate towards the tumor. This poor tumor homing efficiency is one of the limiting factors for NSC-based anti-cancer therapeutic approach and must be address. On this basis, I now propose to study the underlying molecular mechanisms of the inherent tumor-tropic properties of NSCs, which will allow us to develop protocol to further improve the tumor homing efficiency of NSCs. Our preliminary data indicated that migratory subpopulation of NSCs differs significantly from their nonmigratory counterpart based on the level of VEGFR2 and nestin expression. Moreover, blocking VEGFR2/VEGF signaling significantly impaired tumor-tropic migratory properties of NSCs. Thus, further detail understanding of signaling pathways that regulate migratory properties of NSCs will be crucial for development of optimized NSC-based targeted therapy (Aim 1). In addition, the reported immunosuppressive properties of NSCs are a very attractive attribute to their utilization as a cell carrier for novel anti-glioma therapy given that they will allow therapeutic payloads such as oncolytic viruses to be shielded from the host immune response. Therefore, I now propose to characterize the molecular nature of NSC-mediated immunosuppressant in the context of viral infection and examine how it may help to enhance therapeutic efficacy of anti-glioma oncolytic virotherapy (Aim 2). And finally, our preliminary data show that the viability of NSCs is significantly compromised upon ex vivo loading with the oncolytic virus due to replication-mediated carrier cell lysis. This is an essential step for the tumor-specific amplification of the therapeutic viruses, but counter-intuitive for long-term survival and tumor-specific homing of the carrier cells. Based on this, I hypothesize that blocking viral replication transiently during ex vivo loading will enhance the survival, loading capacity and tropism of NSCs for gliomas. In our final specific aim, I now propose to develop an inducible system that will allow us to maximize the ex vivo loading of the oncolytic virus without altering the survival and tropism of the NSCs (Aim 3). In conclusion, the proposed studies have the potential to making an impact beyond neuro-oncology and will accelerate the translational of the stem cell-based therapy in the clinic.

项目概要： 多形性胶质母细胞瘤是一种中枢神经系统的原发性恶性肿瘤，几乎 由于这些肿瘤的播散性，普遍致命。在这种背景下，我们的实验室和其他人 研究了神经干细胞（NSC）独特的亲肿瘤特性，作为一种新的平台 在大脑中靶向输送抗癌药物。然而，尽管有很强的肿瘤趋向性 从 NSC 的表现来看，只有一小部分移植细胞能够向 瘤。这种较差的肿瘤归巢效率是基于 NSC 的抗癌的限制因素之一 治疗方法和必须解决的问题。在此基础上，我现在提出研究 NSCs 固有的亲肿瘤特性的潜在分子机制， 将使我们能够开发进一步提高 NSC 的肿瘤归巢效率的方案。 我们的初步数据表明，NSC 的迁移亚群与它们的迁移亚群存在显着差异。 基于 VEGFR2 和巢蛋白表达水平的非迁移对应物。此外，阻止 VEGFR2/VEGF 信号显着损害 NSC 的肿瘤迁移特性。因此， 对调节 NSC 迁移特性的信号通路的进一步详细了解将是 对于开发优化的基于 NSC 的靶向治疗至关重要（目标 1）。此外，报道称 NSCs 的免疫抑制特性是其作为一种非常有吸引力的属性。 新型抗神经胶质瘤疗法的细胞载体，因为它们将允许治疗有效负载，例如 作为溶瘤病毒，可以免受宿主免疫反应的影响。因此，我现在提议 表征病毒背景下 NSC 介导的免疫抑制剂的分子性质 感染并检查它如何有助于提高抗神经胶质瘤溶瘤药物的治疗效果 病毒疗法（目标 2）。最后，我们的初步数据表明 NSC 的生存能力显着 由于复制介导的载体细胞，体外加载溶瘤病毒时受到损害 裂解。这是治疗病毒肿瘤特异性扩增的重要步骤，但是 对于载体细胞的长期存活和肿瘤特异性归巢来说是违反直觉的。基于此， 我假设在离体加载过程中短暂阻断病毒复制会增强 神经胶质瘤神经干细胞的存活、负载能力和趋向性。在我们最终的具体目标中，我现在 建议开发一种诱导系统，使我们能够最大限度地提高体外负载 溶瘤病毒而不改变 NSC 的存活和向性（目标 3）。总之， 拟议的研究有可能产生超越神经肿瘤学的影响，并将 加速干细胞疗法在临床的转化。