Using FAP to Selectively Target Epithelial Cancers

使用 FAP 选择性靶向上皮癌

基本信息

批准号：
8676477
负责人：
WILLIAM W BACHOVCHIN
金额：
$ 32.51万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676477
关键词：
Ablation Accounting Address Adjuvant Antineoplastic Agents Biological Bone Marrow Bortezomib Breast Cancer Vaccines Cessation of life Cleaved cell Colorectal Cytotoxic agent Dipeptidyl Peptidases Dose-Limiting Drug Targeting Enzymes Epithelial Eragrostis Evaluation Exhibits Failure Family Fibroblasts Goals Growth Hematopoietic Homologous Gene Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Investigation Knockout Mice Knowledge Lung Malignant Neoplasms Membrane Glycoproteins Mesenchymal Modeling Molecular Normal tissue morphology Pancreas Pear Peptide Hydrolases Pericytes Pharmaceutical Preparations Phenotype Problem Solving Prodrugs Proteasome Inhibitor Protein Inhibition Regulation Research Resistance Risk Role Serine Protease Site Solid Staging Stromal Neoplasm Surface T cell response T-Lymphocyte Therapeutic Index Tissues Toxic effect Tumor Antigens Tumor Immunity Tumor Markers Tumor Promotion Veins alanylproline base cancer cell cancer therapy chemotherapeutic agent clinical efficacy cytotoxic design drug discovery fibroblast-activating factor in vivo inhibitor/antagonist killings mouse model prevent prolyl oligopeptidase protein expression response small molecule tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Fibroblast activation protein (FAP) is a serine protease expressed on the surface of tumor-associated fibroblasts (TAFs) in epithelial cancers and expressed to a lesser extent in healthy tissues. FAP appears to promote tumor growth, and FAP+ TAFs appear to suppress tumor killing by effector T cells (Teff). However, the role of FAP proteolytic activity in these effects is not fully understood. For instance, is FAP proteolytic activity involved in immunosuppression by FAP+ TAFs? Is FAP proteolytic activity involved in tumor promotion by non- immune effects? Indeed, it is possible that FAP promotes tumor growth by several mechanisms. Mechanistic knowledge of FAP is needed for evaluation of its potential as a target for drug discovery. Understanding of the possible immunoregulatory functions of FAP is particularly important. Cancer vaccines can prime T cells against tumor antigens; but the immune responses seldom produce durable tumor regression clinically. Immunosuppression of T cells by FAP+ TAFs at the tumor site seems likely to contribute to the failure of cancer vaccines. Consequently, pharmacological agents that inhibit or ablate FAP+ TAFs could relieve immunosuppression and act as adjuvants that enable cancer vaccines to achieve clinical efficacy. To date, the unavailability of pharmacological inhibitors that target FA with selectivity over related serine proteases has hindered investigation of FAP proteolytic activity in cancer. Non-specific inhibitors have yielded results that implicate serine proteases in tumor growth and immune regulation; but the relevant target in vivo remains elusive. Bachovchin et al recently discovered how to make FAP-selective inhibitors and cytotoxic pro-drugs that are targeted by FAP to the tumor site. The agents will be used to probe FAP and FAP+ TAF function in models of epithelial cancer in which FAP is known to promote tumor growth. Investigation of two different pharmacological approaches - FAP inhibition and cytotoxic ablation of FAP+ TAFs - will reduce risk of failure in the early stages of the project. The Specifi Aims include: comparison of antitumor effects achieved by inhibition of FAP activity versus pharmacological ablation of FAP+ TAFs, characterization of the possible immune or non-immune mechanisms of action, and evaluation of the feasibility of FAP-targeted anticancer agents by determining therapeutic index and characterizing mechanism-based toxicities that might arise due to expression of FAP in some normal tissues. It will be important to evaluate any hematopoietic toxicity of FAP- targeted agents that might arise from interactions with FAP-expressing stromal fibroblasts in bone marrow. The proposed research will address basic questions about the functions of FAP in tumor progression and support the long-term goal of developing a FAP-targeted pharmacological approach to cancer treatment.

描述（由申请人提供）：成纤维细胞激活蛋白（FAP）是上皮癌中与肿瘤相关的成纤维细胞（TAF）表达的丝氨酸蛋白酶，在健康组织中的表达程度较小。 FAP似乎促进了肿瘤的生长，FAP+ TAF似乎抑制了效应T细胞杀死肿瘤（TEFF）。但是，FAP蛋白水解活性在这些作用中的作用尚不完全了解。例如，FAP+ TAFS免疫抑制涉及FAP蛋白水解活性吗？ FAP蛋白水解活性是否通过非免疫作用参与肿瘤促进？实际上，FAP可能通过多种机制促进肿瘤生长。需要对FAP的机械知识来评估其作为药物发现目标的潜力。了解FAP可能的免疫调节功能尤其重要。癌症疫苗可以针对肿瘤抗原的T细胞促进T细胞。但是免疫反应很少在临床上产生持久的肿瘤回归。通过FAP+ TAF在肿瘤部位对T细胞的免疫抑制似乎有助于癌症疫苗的衰竭。因此，抑制或消融FAP+ TAF的药理学剂可以缓解免疫抑制并充当佐剂，使癌症疫苗能够达到临床疗效。迄今为止，针对相关丝氨酸蛋白酶的选择性靶向FA的药理学抑制剂的不可用，这阻碍了对癌症FAP蛋白水解活性的研究。非特异性抑制剂产生的结果使丝氨酸蛋白酶在肿瘤生长和免疫调节；但是相关的体内目标仍然难以捉摸。 Bachovchin等人最近发现了如何使FAP选择性的FAP选择性抑制剂和细胞毒性促毒药，这些抑制剂是FAP靶向肿瘤部位的。这些药物将用于在上皮癌模型中探测FAP和FAP+ TAF功能，其中已知FAP促进肿瘤生长。对两种不同的药理学方法的研究 - FAP抑制和FAP+ TAF的细胞毒性消融 - 将降低项目早期阶段失败的风险。该特定目的包括：通过抑制FAP活性与FAP+ TAF的药理消融所获得的抗肿瘤作用的比较，表征可能的免疫或非免疫机制，以及评估FAP靶向抗癌药物的可行性，通过确定基于FAP的染色体的可行性，以确定某些可能的基于抗性的毒性和表达毒性的效率，以使某些效率造成抗毒性的效果。评估FAP靶向剂的任何造血毒性可能是由与表达FAP表达FAP的基质成纤维细胞相互作用而产生的。拟议的研究将解决有关FAP在肿瘤进展中功能的基本问题，并支持开发针对FAP靶向的癌症治疗方法的长期目标。