Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy.
Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy.
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DOI：
10.1158/1535-7163.mct-11-0340
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发表时间：
2012-02
影响因子：
5.7
通讯作者：
Denmeade SR
中科院分区：
文献类型：
--
作者：
Brennen WN;Isaacs JT;Denmeade SR
肿瘤微环境已成为治疗癌症的一种新的化疗策略。这一点以抗血管生成类化合物为最明显的例证。以肿瘤间质内的成纤维细胞为靶点的治疗策略提供了另一种治疗选择。然而，尽管在临床前模型中获得了有希望的数据，但这种策略尚未广泛应用于临床环境，主要是因为缺乏专门针对这一细胞群体的有效治疗方法。成纤维细胞激活蛋白α(FAP)作为靶点选择性地表达于肿瘤间质内的成纤维细胞或肿瘤相关的成纤维细胞上，导致了开发这一新的细胞靶点用于临床的密集努力。FAP是一种膜结合型丝氨酸蛋白酶，属于Pro-寡肽酶家族，具有独特的Pro-后内肽酶活性。直到最近，大多数基于FAP的治疗方法都集中在开发酶活性的小分子抑制剂上。然而，证据表明，FAP在癌症发生中的病理生理学作用可能是高度相关的，这取决于存在的肿瘤微环境的确切性质和所讨论的癌症类型，以确定其促进肿瘤或抑制肿瘤的表型。作为一种替代策略，我们正在利用FAP的限制性表达和独特的底物偏好来开发一种FAP激活的前药，以靶向肿瘤间质中的一种细胞毒化合物的激活。值得注意的是，这种策略将是有效的，独立于FAP在肿瘤进展中的作用，因为它的治疗益处将依赖于FAP在肿瘤微环境中的定位和活性，而不是严格地依赖于对其功能的抑制。
The tumor microenvironment has emerged as a novel chemotherapeutic strategy in the treatment of cancer. This is most clearly exemplified by the antiangiogenesis class of compounds. Therapeutic strategies that target fibroblasts within the tumor stroma offer another treatment option. However, despite promising data obtained in preclinical models, such strategies have not been widely used in the clinical setting, largely due to a lack of effective treatments that specifically target this population of cells. The identification of fibroblast activation protein α (FAP) as a target selectively expressed on fibroblasts within the tumor stroma or on carcinoma-associated fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit. FAP is a membrane-bound serine protease of the prolyl oligopeptidase family with unique post-prolyl endopeptidase activity. Until recently, the majority of FAP-based therapeutic approaches focused on the development of small-molecule inhibitors of enzymatic activity. Evidence suggests, however, that FAP’s pathophysiological role in carcinogenesis may be highly contextual, depending on both the exact nature of the tumor microenvironment present and the cancer type in question to determine its tumor-promoting or tumor-suppressing phenotype. As an alternative strategy, we are taking advantage of FAP’s restricted expression and unique substrate preferences to develop a FAP-activated prodrug to target the activation of a cytotoxic compound within the tumor stroma. Of note, this strategy would be effective independently of FAP’s role in tumor progression because its therapeutic benefit would rely on FAP’s localization and activity within the tumor microenvironment rather than strictly on inhibition of its function.