Development of anti-angiogenesis therapy targeting integrin

针对整合素的抗血管生成疗法的开发

基本信息

批准号：
8631535
负责人：
Zhi-Ren Liu
金额：
$ 41.3万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631535
关键词：
Adverse effects Affect Affinity Angiogenesis Inhibition Angiogenesis Inhibitors Animal Cancer Model Animal Model Anoikis Antibodies Antineoplastic Agents Apoptosis Avastin Binding Biodistribution Biological Biological Models Blocking Antibodies Blood Circulation Blood Vessels Breast Cancer Cell Caliber Cancer Model Cancer Patient Cancer cell line Caspase Cell Line Cells Characteristics Chemicals Cilengitide Clinical Clinical Research Complex Computer Simulation Development Docking Dose Drug Kinetics ERBB2 gene Effectiveness Endostatins Endothelial Cells Exhibits FDA approved Fluorouracil Focal Adhesions Future Goals Human Immune Immunologics Implant In Vitro Induction of Apoptosis Integrins Interferons Knockout Mice Laboratories Lead Ligand Binding Ligands MDA MB 435 Malignant Neoplasms Mammary gland Modeling Molecular Mono-S Mus Mutation Neoplasm Metastasis Normal tissue morphology Nude Mice Ocular Melanoma Organ Paclitaxel Pathway interactions Pharmaceutical Preparations Play Procedures Protein Structure Initiative Proteins Rat-1 Rattus Research Project Grants Role Signal Transduction Site Solid Neoplasm Testing Therapeutic Agents Time Tissues Toxic effect Tumor Angiogenesis Tumor-Derived Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular blood supply Work Xenograft procedure angiogenesis antiangiogenesis therapy bevacizumab cancer therapy chemotherapy clinical application crosslink design dosage in vitro activity mimetics mutant novel pre-clinical protein distribution public health relevance research study success therapeutic angiogenesis therapeutic target tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Solid tumors will not grow beyond 3 - 4 mm in diameter without building up their own blood supply. Due to the essential role of tumor angiogenesis, anti-angiogenesis, mono-therapy or in- combination with other therapeutic agents, represents a very promising approach for cancer treatments. Great successes have been achieved, such as Avastin, a FDA approved anti- angiogenesis drug. However, clinical studies revealed that the cancer patient survival benefits of antiangiogenic drugs have thus far been insignificant. In addition, most current studies in development of anti-angiogenesis agent have been mainly focused on strategies of blocking VEGF/VEGFR signaling. Many agents that are developed against the VEGF/VEGFR pathway often cause unwanted biologic side effects. There is urgent need to develop anti-angiogenesis agents by targeting many other biological pathways that are involved in both stimulation and inhibition of cancer angiogenesis. We have developed a new class of anti-angiogenesis proteins by integrin ¿v¿3 at a novel site, the large pocket formed by the I-domain of ¿v and the PSI domain of ¿3. Computational modeling demonstrated that the domain 1 of rat CD2 and human CD2 spatially fit into the designed site very well. Mutations introduced at the D1-CD2 to bridge several key contacts between designed protein and the integrins optimize the binding of the designed protein with integrin. The designed proteins exhibit strong in vitro activity in induction of apoptosis on endothelial HUVEC cells with no effects on other cells. Tests with tumor nude mice PC-3 xenografts show that the designed proteins strongly inhibit tumor growth. Parallel analyses suggested that our developed protein anti-angiogenesis agents are significantly more effective than Avastin in inhibiting tumor growth. In this proposed research project, we propose experiments to further verify whether the designed protein indeed interact with integrin at the designed site, and whether the designed protein indeed exert its activity by targeting the integrin. We will extensively test the effectiveness of the developed protein anti-angiogenesis agents by various animal models of human cancers. We also design experiments to test whether our developed anti-angiogenesis proteins will have great potency for cancer treatment in combination with other anti-cancer drugs. To facilitate potential future clinical applications, we propose experiments to extensively characterize toxicity and bio-distribution of the protein agents. Our study will lead to development of a new and more effective anti-angigenesis agent for cancer treatment.

描述（由申请人提供）：由于肿瘤血管生成、抗血管生成、单一疗法或与其他疗法联合的重要作用，实体瘤的直径不会生长超过3-4毫米。药物代表了一种非常有前途的癌症治疗方法，已经取得了巨大的成功，例如 FDA 批准的抗血管生成药物阿瓦斯丁 (Avastin)，然而，临床研究表明，迄今为止，抗血管生成药物对癌症患者的生存益处微不足道。此外，目前抗血管生成剂开发的大多数研究主要集中在阻断VEGF/VEGFR信号传导的策略上。针对VEGF/VEGFR途径开发的许多药物常常会引起不良的生物副作用，因此迫切需要开发。通过靶向许多其他参与刺激和抑制癌症血管生成的生物途径，我们开发了一种新的整合素抗血管生成蛋白。 v¿ 3 在一个新位点，由 ¿ 的 I 结构域形成的大口袋v 和 ¿ 的 PSI 域3. 计算模型表明，大鼠 CD2 和人 CD2 的结构域 1 在空间上非常适合设计的位点。在 D1-CD2 处引入的突变可桥接设计的蛋白质和整合素之间的几个关键接触，从而优化设计的蛋白质与整合素的结合。设计的蛋白质在诱导内皮 HUVEC 细胞凋亡方面表现出很强的体外活性，而对其他细胞的肿瘤裸鼠 PC-3 异种移植物的测试表明，设计的蛋白质具有抑制作用。并行分析表明，我们开发的蛋白质抗血管生成剂在抑制肿瘤生长方面比阿瓦斯汀更有效，在这个拟议的研究项目中，我们提出实验来进一步验证设计的蛋白质是否确实与设计位点的整合素相互作用。以及所设计的蛋白质是否确实通过靶向整合素发挥其活性，我们将通过各种人类癌症动物模型广泛测试所开发的蛋白质抗血管生成剂的有效性。有很棒的与其他抗癌药物联合治疗癌症的效力为了促进未来潜在的临床应用，我们建议进行实验来表征蛋白质药物的毒性和生物分布，我们的研究将导致开发一种新的、更有效的抗血管生成药物。癌症治疗剂。