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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：
8295246
负责人：
WILLIAM W BACHOVCHIN
金额：
$ 37.26万
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/8295246
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 Delivery Systems 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 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. PUBLIC HEALTH RELEVANCE: Approved anticancer drugs are limited by toxicity and are notoriously ineffective against solid epithelial cancer (e.g. lung, colorectal, breast and pancreatic), which accounts for the majority of cancer deaths. Fibroblast activation protein (FAP) is an enzyme expressed to a far greater extent in the stromal tissue fibroblasts that promote growth of epithelial tumors than in healthy tissues. FAP and FAP-expressing fibroblasts of the tumor stroma will be investigated as drug targets in cancer in support of the goal of discovering new anticancer drugs.

描述（由申请人提供）：成纤维细胞活化蛋白（FAP）是一种丝氨酸蛋白酶，在上皮癌中表达于肿瘤相关成纤维细胞（TAF）表面，在健康组织中表达程度较低。FAP似乎促进肿瘤生长，而FAP+ TAF似乎抑制效应T细胞（Teff）的肿瘤杀伤。然而，FAP蛋白水解活性在这些作用中的作用尚未完全了解。例如，FAP蛋白水解活性是否参与FAP+ TAF的免疫抑制？FAP蛋白水解活性是否通过非免疫效应参与肿瘤促进？事实上，FAP可能通过几种机制促进肿瘤生长。需要FAP的机制知识来评估其作为药物发现靶点的潜力。了解FAP可能的免疫调节功能尤为重要。癌症疫苗可以引发T细胞对抗肿瘤抗原;但免疫应答很少在临床上产生持久的肿瘤消退。FAP+ TAF在肿瘤部位对T细胞的免疫抑制似乎可能导致癌症疫苗的失败。因此，抑制或消除FAP+ TAF的药理学试剂可以缓解免疫抑制，并作为佐剂使癌症疫苗能够达到临床疗效。迄今为止，无法获得对相关丝氨酸蛋白酶具有选择性的靶向FA的药理学抑制剂，这阻碍了对癌症中FAP蛋白水解活性的研究。非特异性抑制剂已经产生了结果，涉及丝氨酸蛋白酶，肿瘤生长和免疫调节;但体内相关靶点仍然难以捉摸。Bachovchin等人最近发现了如何制造FAP选择性抑制剂和细胞毒性前药，这些药物被FAP靶向到肿瘤部位。这些试剂将用于探测上皮癌模型中的FAP和FAP+ TAF功能，其中已知FAP促进肿瘤生长。研究两种不同的药理学方法- FAP抑制和FAP+ TAF的细胞毒性消融-将降低项目早期阶段的失败风险。具体目标包括：比较通过抑制FAP活性与FAP+ TAF的药理学消融实现的抗肿瘤作用，表征可能的免疫或非免疫作用机制，并通过确定治疗指数和表征可能由于FAP在一些正常组织中表达而产生的基于机制的毒性来评价FAP靶向抗癌剂的可行性。重要的是评价FAP靶向剂的任何造血毒性，其可能由与骨髓中表达FAP的基质成纤维细胞的相互作用引起。这项研究将解决有关FAP在肿瘤进展中的功能的基本问题，并支持开发FAP靶向药物治疗癌症的长期目标。公共卫生关系：批准的抗癌药物受到毒性的限制，并且众所周知对实体上皮癌（例如肺癌、结肠直肠癌、乳腺癌和胰腺癌）无效，这占癌症死亡的大多数。成纤维细胞活化蛋白（FAP）是一种在基质组织成纤维细胞中表达程度远高于健康组织的酶，其促进上皮肿瘤的生长。FAP和肿瘤间质的FAP表达成纤维细胞将作为癌症中的药物靶点进行研究，以支持发现新抗癌药物的目标。