Therapeutic Inhibition of Fibroblast Activation Protein

成纤维细胞激活蛋白的治疗性抑制

基本信息

批准号：
7266362
负责人：
JONATHAN D CHENG
金额：
$ 12.54万
依托单位：
FOX CHASE CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7266362
关键词：
Animal Model Antibodies Antigens Attenuated Binding Biodistribution Biological Assay Carcinoma Cell Adhesion Molecules Cells Chemosensitization Clinical Development Dipeptidyl Peptidases Disruption Doctor of Medicine Drug Kinetics Endopeptidases Engineering Environment Enzyme-Linked Immunosorbent Assay Enzymes Epitopes Fibroblasts Goals Growth Growth Factor HT29 Cells Human Hybridomas Immunization Immunoglobulin G Immunohistochemistry Invasive Laboratory Research Libraries Life Lung Malignant Epithelial Cell Malignant Neoplasms Membrane Glycoproteins Mentors Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Neoplasms Normal tissue morphology Numbers Pan Genus Pathway interactions Peptide Hydrolases Personal Satisfaction Phage Display Play Premalignant Property Protein Binding Protein Overexpression Range Rate Recombinants Research Role Screening procedure Stromal Cells Stromal Neoplasm Structure Surface Plasmon Resonance Techniques Testing Therapeutic Therapeutic Intervention Triad Acrylic Resin Work Xenograft procedure attenuation authority base collagenase expectation fibroblast-activating factor host neoplasm interaction inhibiting antibody innovation neoplastic cell novel novel therapeutics programs protein expression protein function selective expression tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this research program is to develop novel therapeutic strategies targeting the bidirectional interactions between tumor cells and the stromal cells that are found in tumors. The central hypothesis of this proposal is that inhibition of fibroblast activation protein (FAP) proteolytic activity will abrogate the invasive and metastatic capabilities of tumors, leading to attenuated tumor growth and diminished metastatic potential. This hypothesis is based on the highly selective expression of human FAP by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissue. Pathways by which tumor fibroblasts participate in tumor growth can be targeted for disruption by monoclonal antibodies, which can be developed for clinical use. This proposal aims to generate monoclonal antibodies targeting murine FAP, and characterize their binding properties. This has been initiated by immunizing mice with murine FAP, and screening of hybridoma supernatants by ELISA for FAP binding. Antibodies that target FAP have been identified, and will be further characterized by surface plasmon resonance, live cell binding assays, and immunohistochemistry studies. FAP antibodies are also being assessed for inhibition of FAP proteolytic activity by dipeptidyl peptidase assays, enzyme immunocapture assays, and quantitative zymography. FAP inhibitory antibodies will be administered in an animal model to test the hypothesis that inhibition of FAP proteolytic activity inhibits tumor growth and metastases. If FAP inhibitory monoclonal antibodies cannot be produced by conventional immunization and fusion techniques, a human single-chain Fv (scFv) phage display library will be panned for FAP binding and enzymatic function inhibition. Inhibitory scFv fragments will be converted into IgG formats. Disruption of murine FAP proteolytic pathways by inhibitory antibodies resulting in inhibition of tumor growth and metastases will be considered sufficiently significant to warrant the clinical development of a novel therapeutic strategy targeting human cancers that induce FAP proteolytic activity.

描述（由申请人提供）：该研究计划的长期目标是开发针对肿瘤细胞和肿瘤中发现的基质细胞之间的双向相互作用的新型治疗策略。该提议的中心假设是，抑制成纤维细胞激活蛋白（FAP）蛋白水解活性将消除肿瘤的侵袭和转移能力，导致肿瘤生长减弱和转移潜力减弱。该假说基于上皮癌中肿瘤基质成纤维细胞高度选择性表达人 FAP，但上皮癌细胞、正常成纤维细胞或其他正常组织不表达。单克隆抗体可以靶向破坏肿瘤成纤维细胞参与肿瘤生长的途径，并将其开发用于临床。该提案旨在生成针对小鼠 FAP 的单克隆抗体，并表征其结合特性。这是通过用鼠 FAP 免疫小鼠，并通过 ELISA 筛选杂交瘤上清液的 FAP 结合来启动的。靶向 FAP 的抗体已被鉴定，并将通过表面等离振子共振、活细胞结合测定和免疫组织化学研究进一步表征。还通过二肽基肽酶测定、酶免疫捕获测定和定量酶谱法评估 FAP 抗体对 FAP 蛋白水解活性的抑制作用。将在动物模型中施用 FAP 抑制性抗体，以测试抑制 FAP 蛋白水解活性可抑制肿瘤生长和转移的假设。如果无法通过常规免疫和融合技术生产 FAP 抑制性单克隆抗体，则将筛选人单链 Fv (scFv) 噬菌体展示文库用于 FAP 结合和酶功能抑制。抑制性 scFv 片段将转化为 IgG 格式。通过抑制性抗体破坏小鼠 FAP 蛋白水解途径，从而抑制肿瘤生长和转移，将被认为具有足够的意义，足以保证临床开发针对诱导 FAP 蛋白水解活性的人类癌症的新型治疗策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolution of tumor invasiveness: the adaptive tumor microenvironment landscape model.

DOI：
10.1158/0008-5472.can-11-0304
发表时间：
2011-10-15
期刊：
Cancer research
影响因子：
11.2
作者：
Lee HO;Silva AS;Concilio S;Li YS;Slifker M;Gatenby RA;Cheng JD
通讯作者：
Cheng JD

Identification and characterization of the promoter of fibroblast activation protein.

成纤维细胞激活蛋白启动子的鉴定和表征。

DOI：
10.2741/e175
发表时间：
2010
期刊：
Frontiers in bioscience (Elite edition)
影响因子：
0
作者：
Zhang,Jiping;Valianou,Matthildi;Cheng,JonathanD
通讯作者：
Cheng,JonathanD

Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers.

DOI：
10.1021/jm801052f
发表时间：
2009-01-22
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Lo PC;Chen J;Stefflova K;Warren MS;Navab R;Bandarchi B;Mullins S;Tsao M;Cheng JD;Zheng G
通讯作者：
Zheng G

FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells.