Genetically-Modified Neural Stem Cell Based Virotherapy for Invasive Gliomas

项目总结： 多形性胶质母细胞瘤是一种原发于中枢神经系统的恶性肿瘤，几乎 由于这些肿瘤的播散性，通常是致命的。在这种情况下，我们的实验室和其他人 已经研究了神经干细胞(NSCs)作为一种新的治疗平台的独特的肿瘤亲和性 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 由神经干细胞展示，只有一小部分移植细胞能够迁移到 肿瘤。这种较低的肿瘤归巢效率是神经干细胞抗癌的限制因素之一。 治疗方法，必须加以解决。在此基础上，我现在建议研究 神经干细胞固有的促肿瘤特性的潜在分子机制 将使我们能够开发出进一步提高NSCs肿瘤归巢效率的方案。 我们的初步数据显示，神经干细胞的迁移亚群与他们的 基于VEGFR2和Nestin表达水平的非迁移性对应。此外，屏蔽 VEGFR2/VEGF信号转导显著降低NSCs的趋瘤迁移能力。因此， 对调节神经干细胞迁移特性的信号通路将有进一步的详细了解 对优化的基于神经干细胞的靶向治疗的发展至关重要(目标1)。此外，据报道， 神经干细胞的免疫抑制特性是其作为一种 用于新型抗胶质瘤疗法的细胞载体，因为它们将允许治疗有效载荷 作为溶瘤病毒而不受宿主免疫反应的影响。因此，我现在提议 在病毒背景下表征神经干细胞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胶质瘤溶瘤性疾病的治疗效果 病毒治疗(目标2)。最后，我们的初步数据显示，神经干细胞的生存能力显著 由于复制介导的载体细胞，在体外负载溶瘤病毒时受到损害 解体。这是治疗性病毒肿瘤特异性扩增的关键一步，但 对载体细胞的长期存活和肿瘤特异性归巢的看法与直觉相反。在此基础上， 我推测，在体外加载过程中暂时阻止病毒复制将增强 神经干细胞在脑胶质瘤中的存活、载量和趋向性。在我们最终的具体目标中，我现在 建议开发一种可诱导的系统，使我们能够最大限度地提高体外负荷 溶瘤病毒而不改变神经干细胞的存活和趋向性(目标3)。总而言之， 拟议中的研究有可能产生超越神经肿瘤学的影响，并将 加快干细胞治疗在临床上的转化。

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.