Using FAP to Selectively Target Epithelial Cancers

描述(申请人提供)：成纤维细胞激活蛋白(FAP)是一种丝氨酸蛋白酶，表达在上皮性肿瘤的肿瘤相关成纤维细胞(TAFs)表面，在健康组织中表达程度较低。FAP似乎促进了肿瘤的生长，而FAP+TAFs似乎抑制了效应T细胞(TEF)对肿瘤的杀伤。然而，FAP蛋白水解酶活性在这些效应中的作用尚不完全清楚。例如，FAP蛋白水解酶活性是否参与FAP+TAFs的免疫抑制？FAP蛋白分解活性是否参与了非免疫效应促进肿瘤的发生？事实上，FAP可能通过几种机制促进肿瘤生长。需要对FAP的机理知识进行评估，以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。癌症疫苗可以激发T细胞对抗肿瘤抗原；但在临床上，这种免疫反应很少产生持久的肿瘤消退。肿瘤部位FAP+TAFs对T细胞的免疫抑制似乎是肿瘤疫苗失败的原因之一。因此，抑制或去除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效果。到目前为止，靶向FA而不是相关丝氨酸蛋白酶的药物抑制剂的缺乏阻碍了对FAP在癌症中的蛋白分解活性的研究。非特异性抑制剂的研究结果表明，丝氨酸蛋白酶在 肿瘤生长和免疫调节；但体内的相关靶点仍然难以捉摸。巴霍夫钦等人最近发现了如何制造FAP选择性抑制剂和细胞毒前药，这些药物是FAP靶向肿瘤部位的。这些试剂将用于探索FAP和FAP+TAF在已知FAP促进肿瘤生长的上皮性癌症模型中的功能。研究两种不同的药理学方法--抑制FAP和细胞毒性消融FAP+TAFs-将降低项目早期阶段的失败风险。这些特异性的目的包括：比较抑制FAP活性与药物消融FAP+TAFs的抗肿瘤效果，表征可能的免疫或非免疫作用机制，以及通过确定治疗指数和表征FAP在某些正常组织中的表达可能产生的基于机制的毒性来评价FAP靶向抗癌药物的可行性。评估FAP靶向药物可能与骨髓中表达FAP的基质成纤维细胞相互作用而产生的任何造血毒性将是重要的。这项拟议的研究将解决有关FAP在肿瘤进展中的功能的基本问题，并支持开发FAP靶向的癌症治疗药理学方法的长期目标。

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.