An innovative modular strategy for highly specific elimination of human osteosarcomas

用于高度特异性消除人类骨肉瘤的创新模块化策略

• 批准号: 9914093
• 负责人: TIMOTHY P CRIPE
• 金额: $ 20.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914093
• 关键词: Affect; Algorithms; Animal Model; Bacterial Toxins; Benign; C-terminal; Cancer Patient; Cancer cell line; Catalytic Domain; Cell Line; Cells; Clinical Research; Cytoplasm; DNA; Data; Development; Diphtheria Toxin; Disease; ERBB2 gene; Ensure; Epidermal Growth Factor Receptor; Evaluation; Genes; Goals; Government; Health; Herpesvirus 1; Homo; Human; Immune response; Immunocompetent; Immunotoxins; In Vitro; Injections; Intelligence; Knowledge; Libraries; Lice; Life; Malignant Bone Neoplasm; Malignant Neoplasms; Measles Vaccine; Mediating; Membrane; Methodology; Mission; Modeling; Mus; N-terminal; Normal Cell; Nude Mice; Oncolytic; Oncolytic viruses; Outcome; Pathway interactions; Patients; Persons; Plasmids; Positioning Attribute; Recombinants; Research; Safety; Simplexvirus; Technology; Testing; Therapeutic; Toxic effect; Toxin; Trans-Splicing; United States National Institutes of Health; Vaccinia Vaccine; Viral Genome; Virus; Xenograft Model; Xenograft procedure; alpha Toxin; anthrax toxin; anticancer activity; base; cancer cell; cancer therapy; cancer type; clinical implementation; clinically relevant; design; empowered; homograft; improved; in vivo; innovation; intein; mortality; mouse model; novel; novel strategies; novel therapeutics; osteosarcoma; preclinical study; receptor; reconstitution; response; tool; tumor; viral DNA

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.

项目总结/摘要 癌症是国家和全球一级死亡的主要原因，因此有必要制定 安全有效的治疗方法。现有的治疗方法不允许治愈三分之一的局部 骨肉瘤是最常见的骨癌类型，四分之三的患者患有转移性疾病。 当前提案的直接目标是根据以下内容制定和验证新战略的可行性： 溶瘤病毒和修饰的蛋白质毒素的组合，用于选择性消除 体外骨肉瘤细胞和初步动物模型。该提案背后的长期目标是 将该策略转化为一种新的治疗平台，其效率和选择性提高， 各种人类癌症。溶瘤病毒作为一种强有力的工具出现在抗肿瘤治疗中。类似地， 细菌毒素的出色的杀伤效率和选择性使它们能够转化为 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：i）缺乏真正的癌症- 用于将细菌毒素递送至癌细胞的特异性受体，和ii）肿瘤对 临床相关的溶瘤病毒（HSV 1、牛痘和麻疹疫苗病毒等）。这些限制将 这一提议的中心假设提出了挑战，即溶瘤病毒的毒性可以通过以下方式增强： 一种新型的嵌合免疫毒素，其能够增加对消除敏感的范围， 骨肉瘤癌症而不损害靶向的选择性。毒素会被改造成 减少非特异性靶向并确保完全控制选择性溶瘤剂的治疗效力 病毒该提案的直接焦点将是单纯疱疹病毒的HSV-Q溶瘤衍生物 以及一种通过炭疽毒素（Atx）进入途径进入癌细胞的强效毒素，该途径重新靶向TEM 8， EGFR和HER 2受体在骨肉瘤和其他类型的癌细胞上富集。拟议 将在体外对创新概念进行彻底评价（目标1），并对其效率和选择性进行测试 对正常细胞和骨肉瘤细胞系（Aim 2）的培养物。目标1和2中获得的数据将 应用于进行评价溶瘤病毒和经修饰的抗肿瘤药物的联合作用的初步研究。 毒素对异种和同种移植小鼠模型中局部人和小鼠骨肉瘤的作用。如果成功， 这些努力将导致一种新的方法的特殊权力，选择性和安全性。