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.

项目概要/摘要 癌症是国家和全球范围内死亡的主要原因，因此需要开发 有效且安全的治疗方法。现有疗法无法治愈三分之一的局部局限性患者 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。 当前提案的近期目标是开发并验证一种新策略的可行性，该策略基于 溶瘤病毒和修饰的蛋白质毒素的组合，用于选择性消除 体外和初步动物模型中的骨肉瘤细胞。该提案背后的长期目标是 将该策略转化为一种提高效率和选择性的新型治疗平台，可针对 各种人类癌症。溶瘤病毒成为抗癌治疗的强大工具。同样， 出色的杀灭效率和对细菌毒素的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：i）真正的癌症的稀缺性 ii) 肿瘤对细菌毒素的异质反应 临床相关溶瘤病毒（HSV1、牛痘和麻疹疫苗病毒等）。这些限制将 受到该提案的中心假设的挑战，即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，能够增加易被消除的范围 骨肉瘤癌症而不影响靶向的选择性。毒素将以某种方式被修改 减少非特异性靶向并确保在选择性溶瘤药物的治疗效力下完全控制 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 以及一种强效毒素，可通过炭疽毒素 (Atx) 进入途径重新定位至 TEM8 进入癌细胞， EGFR 和 HER2 受体在骨肉瘤和其他类型的癌细胞中富集。拟议的 创新概念将在体外进行彻底评估（目标1），并测试其效率和选择性 对正常细胞和骨肉瘤细胞系培养物的影响（Aim2）。目标 1 和 2 中获得的数据将是 用于评估溶瘤病毒和修饰病毒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类和小鼠骨肉瘤的作用。如果成功的话， 这些努力将带来一种具有卓越威力、选择性和安全性的新方法。