An innovative modular strategy for highly specific elimination of human osteosarcomas

项目摘要/摘要 癌症是国家和全球一级死亡的主要原因，这需要发展。 有效而安全的治疗方法。现有的治疗方法不允许治愈三分之一的局部性脑出血患者 骨肉瘤，最常见的骨癌类型，以及四分之三的转移性疾病患者。 目前提案的近期目标是在以下基础上制定和核实新战略的可行性 溶瘤病毒和修饰蛋白类毒素的组合，用于选择性清除 骨肉瘤细胞的体外培养和动物模型的初步建立。这项提议背后的长期目标是 将该策略转变为一种新的治疗平台，提高了效率和选择性，可针对 各种人类癌症。溶瘤病毒成为抗癌治疗的有力工具。类似地， 细菌毒素出色的杀灭效率和选择性使其能够转化为 免疫毒素。然而，这两种技术的广泛应用受到以下因素的限制：1)缺乏真正的癌症-- 向癌细胞运送细菌毒素的特异性受体和II)肿瘤对 临床上相关的溶瘤病毒(HSV1、牛痘和麻疹疫苗病毒等)。这些限制将 受到以下中心假设的挑战：溶瘤病毒的毒性可以通过以下方式增强 一种新型嵌合免疫毒素，可增加易感消除范围 在不影响靶向选择性的情况下治疗骨肉瘤。毒素将以一种方式进行修改以 减少非特异性靶向，并确保在选择性溶瘤的治疗效力下完全控制 病毒。这项提案的直接焦点将是单纯疱疹病毒的HSV-Q溶瘤衍生物 以及一种被调整为通过重定向到TEM8的炭疽毒素(ATX)进入途径进入癌细胞的有效毒素， EGFR和HER2受体在骨肉瘤和其他类型的癌细胞上富含。建议数 创新的概念将在体外进行彻底的评估(目标1)，并将测试其效率和选择性 在正常细胞和骨肉瘤细胞系(AIM2)的培养上。在目标1和目标2中获得的数据将是 应用于评价一种溶瘤病毒和一种改良的 毒素对异种和同种小鼠移植模型中人和小鼠局部骨肉瘤的影响。如果成功， 这些努力将导致一种新的方法，具有非凡的威力、选择性和安全性。

PROJECT SUMMARY/ABSTRACT Cancers are a leading cause of mortality at the national and global levels that necessitates the development of potent and safe therapeutics. Existing therapies do not allow curing one third of patients with localized osteosarcoma, the most common type of bone cancer, and three fourths of patients with metastatic disease. The immediate goals of the current proposal are to develop and verify feasibility of a novel strategy, based on the combination of oncolytic viruses and modified proteinaceous toxins, for selective elimination of osteosarcoma cells in vitro and in preliminary animal models. The long-term goal behind the proposal is to convert the strategy into a novel therapeutic platform of improved efficiency and selectivity, tunable against various human cancers. Oncolytic viruses emerged as a powerful tool in anti-cancer therapy. Similarly, the outstanding killing efficiency and selectivity of bacterial toxins has empowered their conversion to immunotoxins. Yet, the broad application of both technologies is restricted by i) a scarcity of truly cancer- specific receptors for delivery of bacterial toxins to cancer cells and ii) heterogeneous response of tumors to clinically relevant oncolytic viruses (HSV1, vaccinia and measles vaccine viruses, etc.). These limitations will be challenged by the central hypothesis of the proposal that the toxicity of oncolytic viruses can be boosted by a novel type of chimeric immunotoxins enabling to increase the range of susceptible to elimination osteosarcoma cancers without compromising the selectivity of targeting. The toxin will be modified in a way to reduce non-specific targeting and assure full control under the therapeutic potency of a selective oncolytic virus. The immediate focus of this proposal will be on the HSV-Q oncolytic derivative of Herpes Simplex Virus and a potent toxin tuned to enter cancer cells via the Anthrax toxin (Atx) entry pathway retargeted to TEM8, EGFR, and HER2 receptors enriched on osteosarcomas and other types of cancer cells. The proposed innovative concept will be thoroughly evaluated in vitro (Aim 1) and its efficiency and selectivity will be tested on cultures of normal cells and osteosarcoma cell lines (Aim2). The data obtained in the Aims 1 and 2 will be applied to conduct preliminary studies on evaluating a combined action of an oncolytic virus and a modified toxin on localized human and mouse osteosarcomas in xeno- and homograft mouse models. If successful, these efforts will lead to a new methodology of exceptional power, selectivity, and safety.