Enhancement of Viral Spread by Modulation of Glioma Extracellular Matrix

描述（由申请人提供）：本提案的最终目标是开发一种新型溶瘤病毒，以增强脑肿瘤的治疗。肿瘤的OV治疗依赖于病毒的癌症特异性复制，导致肿瘤破坏，对邻近的非肿瘤组织具有最小的毒性。在恶性胶质瘤患者中进行的5项临床试验的结果显示了这种新治疗方式的相对安全性。然而，显著疗效的证据仍有待确定。通过肿瘤细胞的无效病毒扩散可导致病毒扩散不良，因此不允许有效的肿瘤细胞感染和溶瘤。努力增加肿瘤内的病毒传播应导致改善的疗效。我们认为，胶质瘤细胞外基质（ECM）构成了一个重要的障碍，有效的病毒通过肿瘤的传播，因此限制了它的疗效。在我们的初步实验中，我们已经测试了ECM调节酶对胶质瘤中OV分散的影响。使用蛋白酶来增强病毒传播已经过测试，并且已经在皮下肿瘤模型中显示出功效。然而，由于蛋白酶在脑中的表达可导致与肿瘤相关的毒性，因此尚未测试它们在颅内神经胶质瘤中的功效。最近，透明质酸酶与腺病毒的共同给药已经显示出增加的病毒传播和对小鼠皮下肿瘤的治疗功效。然而，透明质酸酶的表达增强了星形胶质细胞的反应性，限制了其在颅内胶质瘤中的应用。在这里，我们建议创建一个新的双武装OV，可以选择性地感染和破坏神经胶质瘤细胞，也表达了以前未经测试的神经胶质瘤ECM调节酶，以提高病毒的传播。先前的研究表明，即使在大鼠大脑中重复注射这种纯化的酶也不会产生毒性。我们相信这项研究非常重要，因为之前尚未测试过使用这种ECM调节酶来增强OV传播和功效。公共卫生相关性：美国癌症协会预测，将有12740人死于脑/神经系统癌症。尽管有几十年的研究，恶性胶质瘤患者的预后仍然很差。溶瘤病毒疗法是一种实验性治疗，目前正在临床试验中评估其对脑肿瘤的疗效。通过肿瘤的无效病毒传播被认为是这种疗法成功的主要障碍之一。这项资助中概述的拟议研究非常重要，因为它将导致开发一种新型的双臂OV，这种OV可以选择性地杀死胶质瘤细胞，并分泌一种胶质瘤ECM调节酶，从而增强这种治疗方式。这将有助于将溶瘤病毒疗法转化为有效的肿瘤治疗。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to develop a novel oncolytic virus to enhance therapy of brain tumors. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from the 5 clinical trials in patients with malignant glioma have shown the relative safety of this novel treatment modality. However evidence for significant efficacy remains to be established. Inefficient viral dispersal through the tumor interstitium can lead to poor viral spread hence not permitting efficient tumor cell infection and oncolysis. Efforts to increase viral spread within the tumor should lead to improved efficacy. We believe that glioma extracellular matrix (ECM) poses a significant barrier for efficient viral 'spread through the tumor, and hence limits its efficacy. In our preliminary experiments we have tested the effect of an ECM modulating enzyme on OV dispersal in glioma. The use of proteases to enhance viral spread has been tested and has shown efficacy in subcutaneous tumor models. However since the expression of proteases in the brain can result in toxicity related to hemorrhaging, they have not been tested for efficacy in intracranial gliomas. More recently co-administration of hyaluronidase with adenovirus has shown increased viral spread and therapeutic efficacy against subcutaneous tumors in mice. However the expression of hyaluronidase elicits astrocytic reactivity which limits its usage for intracranial gliomas. Here we propose to create a novel dually armed OV that can selectively infect and destroy glioma cells and also expresses a previously untested glioma ECM modulating enzyme to enhance viral spread. Previous studies have shown that even repeated injections of this purified enzyme within the rat brain resulted in no toxicity. We believe this study is highly significant as the use of such an ECM modulating enzyme to enhance OV spread and efficacy has not been previously tested. PUBLIC HEALTH RELEVANCE: The American Cancer Society predicts that there will be 12, 740 deaths due to cancers of the brain/nervous system. Despite decades of research prognosis for patients suffering from malignant gliomas remains poor. Oncolytic viral therapy is an experimental treatment which is currently being evaluated in clinical trials for efficacy against brain tumors. Inefficient viral spread through the tumor is thought to be one of the major impediments in the success of this therapy. The proposed research outlined in this grant is highly significant because it will result in the development of a novel dually armed OV that can selectively kill glioma cells and also secrete a glioma ECM modulating enzyme that will result in enhancement of this therapeutic modality. This will help translate oncolytic viral therapy into an efficacious treatment for tumors.