Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy

Abstract

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.

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

“…In addition, we fused the DR5 agonistic antibody to an anti-FAP-binding moiety to take advantage of FAP expression in the tumor stroma as an alternative mechanism to promote hyperclustering of DR5 in a targeted manner. The tumorassociated stroma contributes to a significant proportion of the mass of many malignancies (14) and the stromal fibroblasts play an important role in the development, growth and metastasis of carcinomas (40)(41)(42). FAP, normally restricted in healthy adult tissue (except in granulation tissue, e.g., during wound healing), is expressed in tumor stromal fibroblasts of more than 90% of epithelial cancers (15,16,43), and therefore is an ideal candidate for targeted delivery of cancer therapeutics.…”

“…Fibroblast-activation protein (FAP) is a homodimeric, singlepass type II membrane protein expressed in reactive stromal fibroblasts of more than 90% of epithelial malignancies, including breast, colorectal, and lung cancers and on malignant mesenchymal cells of bone and soft tissue sarcomas (14)(15)(16). Here, we exploited FAP expression on the tumor stroma to develop novel bispecific antibodies (BsAb) consisting of a DR5 agonist and anti-FAP antibody fusion to enhance targeted delivery of the DR5 agonist, induce avidity-driven DR5 hyperclustering and activate the extrinsic apoptotic pathway specifically in tumor cells.…”

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

“…The absence of FAP in normal ovaries and its presence in ovarian cancer makes FAP a very attractive therapeutic target in EOC. Prior research on small molecular inhibition of FAP seemed ineffective, but recent studies targeting FAP using a novel FAP-activated prodrug, a drug that alters the activation of a cytotoxic compound in the tumor stroma, have reported promising results [10,31]. Even though extensive preclinical testing is required before FAP targeting can be implemented in clinical trials, early results are extremely encouraging [10,31].…”

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

“…FAP has a unique post-prolyl endopeptidase activity to cleave the dipeptide at NH2-terminal [84,85]. Hence, FAP-α is known to give shape to microenvironment which promotes growth as well as invasion of tumor through degrading ECM [86][87][88]. Ji et al designed the ferritin-based FAP-α responsive fluorescence probe for the imaging of CAF-positive cancers.…”