Biomedical Engineering Reference
In-Depth Information
of cancers, fibrosis, and inflammation, as a strategy to selectively eliminate
diseased cells.
As discussed, FAP enzyme functions involved in tumorigenesis could
potentially be blocked by an FAP inhibitor, without influencing extra-enzy-
matic effects. Such FAP inhibitors reduce FAP peptidase activity at their
specific sites of action. Inhibiting the endopeptidase activity of FAP on a2-
antiplasmin may enhance wound healing and reduce adhesions via increased
fibrinolysis. On the other hand, inhibiting the collagenase enzymatic activity of
FAP could reduce ECM protein degradation and cancer-cell migration.
Although the exact mechanisms of the involvement of FAP enzyme activity in
cancer cells are yet to be elucidated, therapeutic approaches using FAP inhi-
bitors show promise. FAP Inhibitors
In vivo data on FAP inhibitors should be treated with caution, as all such data
have been generated using inhibitors of FAP that also competitively inhibit
DPP-4. Val-Boro-Pro (PT100), a prolyl boronic acid derivative that competi-
tively inhibits the activity of all DPP-4 enzyme family members, 151 is the first
inhibitor of FAP enzymatic activity evaluated for clinical use. Val-Boro-Pro
attenuates tumor growth in a variety of tumor models in mice. 116,131 However,
a Phase II trial using this inhibitor in patients with metastatic colorectal cancer
showed little clinical ecacy. 152 The inhibitor Glu-Boro-Pro (PT630) inhibits
both FAP and DPP-4 and inhibits tumor growth when orally administered to
mice. 125,152 Furthermore, cell proliferation is significantly reduced in lung and
colon tumors from animals treated with Glu-Boro-Pro compared with those
treated with the DPP-4 selective inhibitor, vildagliptin. 153 It was also shown
that FAP inactivation indirectly inhibits tumor-cell proliferation, increases
accumulation of collagen, decreases myofibroblast content, and decreases
blood-vessel density in these tumors. 153 These data suggest a potential use for
FAP inhibition in the treatment of patients with FAP-positive tumors.
FAP is strongly expressed in synovial fibroblasts and chondrocytes from
rheumatoid arthritis patients. 143,144 Enzymatic inhibition of both FAP and
DPP-4 in mice, using Glu-Boro-Pro, significantly promotes the invasion of
synovial fibroblasts into co-transplanted human cartilage. 154 This indicates a
central role for the activity of FAP and DPP-4 in protecting cartilage against
invasion by synovial fibroblasts in rheumatoid arthritis. However, whether
FAP has a direct role in cartilage degradation remains unclear, since the major
protein constituent of cartilage is type II collagen, which FAP does not
degrade. 120
Thus, as both Val-BoroPro and Glu-BoroPro have shown promise, there is
a need for FAP-selective inhibitors to provide further insight into the role
of this protein in vivo and its clinical potential. A study on the substrate
specificity of FAP defined it as an endopeptidase preferentially cleaving Gly-
Pro. 122 The endopeptidase substrate preference of FAP was exploited to design
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