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（通过应用程序提供）：实体瘤不会在直径3-4毫米以上生长，而无需建立自己的血液供应。由于肿瘤血管生成的重要作用，抗血管生成，单疗法或与其他治疗剂的结合是癌症治疗的一种非常有前途的方法。已经取得了巨大的成功，例如Avastin，FDA批准的抗血管生成药物。然而，临床研究表明，抗血管生成药物的癌症患者生存益处迄今为止并不重要。此外，大多数抗血管生成剂开发的研究主要集中在阻断VEGF/VEGFR信号传导的策略上。许多针对VEGF/VEGFR途径开发的药物通常会引起不必要的生物副作用。迫切需要通过针对许多其他参与刺激和抑制癌症血管生成的生物学途径来发展抗血管生成剂。我们已经通过整合素€3开发了一类新的抗血管生成蛋白在一个新颖的位置，由„ V的I-Domain形成的大口袋和€3的PSI结构域形成。计算建模表明，大鼠CD2的域1和人类CD2的域1在空间上非常适合设计的位点。在D1-CD2上引入的突变是为了弥合设计蛋白质与整合素之间的几个关键接触，从而优化了设计蛋白与整合素的结合。该设计的蛋白质表现出强烈的体外活性诱导内皮HUVEC细胞凋亡，对其他细胞没有影响。肿瘤裸鼠PC-3异种移植物的测试表明，设计的蛋白质强烈抑制肿瘤的生长。平行分析表明，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，我们提出了实验，以进一步验证设计蛋白是否确实在设计的位点与整合蛋白相互作用，以及该设计蛋白是否确实通过靶向整合素来发挥其活性。我们将通过各种人类癌症模型广泛测试开发的蛋白质抗血管生成剂的有效性。我们还设计了实验，以测试我们开发的抗血管生成蛋白是否与其他抗癌药物结合使用癌症治疗的效力很大。为了促进潜在的未来临床应用，我们建议实验以广泛的特征蛋白质剂的毒性和生物分布。我们的研究将导致开发一种用于癌症治疗的新的，更有效的抗原作用。