Using FAP to Selectively Target Epithelial Cancers

使用 FAP 选择性靶向上皮癌

• 批准号: 8528521
• 负责人: WILLIAM W BACHOVCHIN
• 金额: $ 33.5万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 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/8528521
• 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

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）：成纤维细胞活化蛋白（FAP）是一种丝氨酸蛋白酶，表达于上皮癌中肿瘤相关成纤维细胞（TAFs）表面，在健康组织中表达较少。FAP似乎可以促进肿瘤生长，而FAP+ taf似乎可以抑制效应T细胞（Teff）对肿瘤的杀伤作用。然而，FAP蛋白水解活性在这些效应中的作用尚不完全清楚。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作用参与肿瘤促进？事实上，FAP可能通过几种机制促进肿瘤生长。为了评估FAP作为药物发现靶点的潜力，需要了解FAP的机理。了解FAP可能的免疫调节功能尤为重要。癌症疫苗可以激发T细胞对抗肿瘤抗原；但免疫应答在临床上很少产生持久的肿瘤消退。FAP+ TAFs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，抑制或切除FAP+ TAFs的药物可以缓解免疫抑制，并作为佐剂使癌症疫苗达到临床疗效。迄今为止，缺乏选择性靶向FA而非相关丝氨酸蛋白酶的药理学抑制剂，阻碍了对癌症中FAP蛋白水解活性的研究。非特异性抑制剂产生的结果涉及丝氨酸蛋白酶