Engineering a multispecific receptor antagonist to inhibit cancer metastasis

设计多特异性受体拮抗剂来抑制癌症转移

基本信息

批准号：
8749811
负责人：
JENNIFER R COCHRAN
金额：
$ 20.83万
依托单位：
STANFORD 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：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8749811
关键词：
Address Adhesions Affinity Agglutinins Antibodies Avidity Binding Binding Proteins Biochemical Biochemistry Biological Biological Assay Biological Process Breast Cancer Cell Cause of Death Cell Proliferation Cell Surface Receptors Cells Clinical Research Coupled DU145 Development Diagnostic Neoplasm Staging Disease Disseminated Malignant Neoplasm Engineering Epitopes Extracellular Matrix Degradation FDA approved Flow Cytometry Glioblastoma Goals Growth Growth Factor Human Individual Length Libraries Ligand Binding Ligands MDA MB 231 Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of prostate Measures Mediating Methods Molecular and Cellular Biology Mus Neoplasm Metastasis Partner in relationship Patients Peptides Pharmaceutical Preparations Phosphorylation Process Protein Engineering Proteins Relative (related person)Resistance Signal Pathway Signal Transduction Site Specificity Surface Surface of the Prostate Testing Therapeutic Therapeutic Intervention Treatment Efficacy United States Urokinase Urokinase Plasminogen Activator Receptor Variant Vitronectin Yeasts aggressive therapy angiogenesis base cancer cell cancer type chemotherapy combinatorial drug development effective therapy flexibility fluorophore inhibitor/antagonist innovation malignant breast neoplasm migration mutant neoplastic cell neovasculature novel novel strategies overexpression prevent prostate cancer cell public health relevance receptor receptor binding receptor expression research and development small molecule somatomedin B success therapeutic protein therapeutic target tumor tumor growth tumor progression tumorigenesis

项目摘要

The urokinase-type plasminogen activator receptor (uPAR) has been found to be overexpressed on the surface of cancer cells, as well as their associated neovasculature, in virtually every cancer type tested, including primary, metastatic, and chemotherapy-resistant cancers. uPAR is an important master regulator that drives extracellular matrix degradation and angiogenesis, and cancer cell proliferation, adhesion, and migration. These processes in turn allow rapid tumor growth and metastasis to other sites in the body. Clinical studies indicate overexpression of uPAR and its soluble ligand uPA are independent predictors of low diseasefree and overall survival. Thus, uPAR is an extremely attractive target for therapeutic intervention; however, the absence of an FDA-approved drug that inhibits uPAR highlights a critical need for new approaches to effectively block the activity of this receptor. We will apply our expertise in molecular and cellular biology, biochemistry, and protein engineering to develop a novel first-in-class biologic capable of effectively blocking uPAR-mediated cancer growth, metastasis, and tumor-associated angiogenesis. Numerous uPAR antagonists have been developed over the last two decades, including small molecules, peptides, protein ligands, and antibodies. However, the efficacies of these inhibitors have been limited owing to their low affinity relative to the native uPAR ligands, and/or their inability to effectively block uPAR functions that drive cancer growth and metastasis. Protein engineering, combined with multispecific target binding, will generate in uPAR inhibitors with orders of magnitude higher binding affinity compared to previously developed antagonists. The resulting biologics have exciting potential to overcome critical barriers that have prevent development of successful uPAR-targeted therapeutics, and would represent a potential breakthrough for targeted therapy of aggressive cancers.

尿激酶型纤溶酶原活化剂受体（UPAR）已被发现在癌细胞的表面及其相关的新生血管，几乎在每种测试的癌症类型中，包括原发性，转移性和耐化疗的癌症。 UPAR是一个重要的主调节器驱动细胞外基质降解和血管生成以及癌细胞增殖，粘附和迁移。这些过程反过来允许肿瘤的快速生长和转移到体内其他部位。临床研究表明UPAR及其可溶性配体的过表达是无病低的独立预测指标和整体生存。因此，UPAR是治疗干预的极具吸引力的目标。但是，缺乏FDA批准的药物，该药物抑制UPAR强调了对新方法的关键需求有效阻断该受体的活性。我们将在分子和细胞生物学上应用我们的专业知识，生物化学和蛋白质工程，以开发一种能够有效阻止的新型一类生物学 UPAR介导的癌症生长，转移和与肿瘤相关的血管生成。许多UPAR对手在过去的二十年中已经开发了，包括小分子，肽，蛋白质配体和抗体。但是，这些抑制剂的效率由于相对于其低亲和力而受到限制本机UPAR配体和/或它们无法有效阻止驱动癌症生长和的UPAR功能转移。蛋白质工程以及多特异性靶标结合将在UPAR抑制剂中产生与先前开发的拮抗剂相比，结合亲和力的数量级高。结果生物制剂具有令人兴奋的潜力来克服阻止成功发展的关键障碍靶向UPAR靶向治疗方法，这将代表针对性的攻击性治疗的潜在突破癌症。