On The Edge of Validation – Cancer Protease Fibroblast Activation Protein

Abstract

Numerous studies implicate the prolyl peptidase, fibroblast activation protein (FAP) in tumorigenesis; however, FAP-selective inhibitors have not yet been developed to fully validate FAP as a therapeutic target. Herein, we review recent efforts aimed at validating and inhibiting FAP for cancer therapy and highlight future directions for successful targeting of this prolyl peptidase.

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

“…The corresponding Glu203 and Glu204 in FAP have a different orientation to accommodate endopeptidase substrates, and thus also allow acylated P2-amines to enter FAP's active center. 15 As reported earlier, selectivity of N-acylated inhibitors with respect to the endopeptidase PREP is far less evident. Nonetheless, a comparison of initial 'hit' 3 (SI [ 'lead' 7 (SI [FAP/PREP] = 85) indicates that selectively optimizing for FAP affinity is possible.…”

“…Most research effort in the domain of FAP-inhibitor discovery to date has been centered around pyrrolidine-2-boronic acid derivatives. 15,16 These compounds in general also display significant affinity for one or several DPPs. 15,16 The most representative of this class, Val-boroPro (Talabostat, PT-100) 1 has reached phase II clinical trials (Table 1).…”

“…15,16 These compounds in general also display significant affinity for one or several DPPs. 15,16 The most representative of this class, Val-boroPro (Talabostat, PT-100) 1 has reached phase II clinical trials (Table 1). It was evaluated as a therapeutic drug for, among others, metastatic kidney cancer, pancreatic adenocarcinoma, nonsmall cell lung cancer, and chronic lymphocytary leukemia (Figure 1).…”

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…The formation of CAFs involves several important features: (a) the expression of fibroblast markers vimentin, FSP1 and FAP; (b) the expression of activation marker α‐SMA; (c) the expression of aggressive/invasive markers including TNC; (d) an increase in cytokine and growth factor expression including IL‐8, IL‐6, SDF‐1, VEGF, TGF‐β, HGF, and FGF‐2; and (e) the reprogramming of ECM proteins and matrix remodeling proteins 4, 35, 48, 49, 50, 51, 52, 53. Interestingly, we have observed that the mRNA expression of α‐SMA, collagen I, or HIF‐1α was not altered by H. pylori ( cagA−vacA−) in contrast to the moderate increase in HSP‐70 mRNA expression possibly due to the “cytoprotective” properties of bacterial wall product LPS 54, 55.…”

Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

“…The natural substrates of FAP are still not completely identified, but the protease is capable of cleaving N-terminal dipeptides from polypeptides with proline or alanine in the penultimate position (8) and also has collagenase activity (9)(10)(11). The dipeptidyl-peptidase activity of FAP is one of the mediators of tumor progression (12), extracellular matrix remodeling (13)(14)(15)(16)(17)(18), and metastasis formation (10,19), but recent studies strongly suggest additional effects of FAP in the absence of its enzymatic activity (20) by hitherto unclear mechanisms. Very recently, FAP-expressing stromal cells have been shown to suppress antitumor immunity (21), adding yet another aspect to the manifold contributions of FAP to tumor growth.…”