Biomedical Engineering Reference
In-Depth Information
human breast and prostate cancer xenografts with minimal toxicity to the host
mice. 161 The current usefulness of this approach is limited to local intratumoral
delivery of the prodrug, but potentially may be exploited further using
appropriate delivery systems and might be exploited for fibrosis therapy.
Another related strategy, similarly dependent on both FAP enzyme activity
and expression patterns, utilises a FAP-triggered photodynamic molecular
beacon which is highly specific. It has photocytotoxic effects when injected
directly into FAP-expressing tumors. 162 Strategies that remove FAP-expressing
cells may prove to be very effective. Breast-cancer stromal cells that express the
greatest amounts of FAP appear to be a significant cell type most prone to
epithelial-mesenchymal transition. 163 Using a mouse genetically engineered so
that FAP-positive cells can be selectively killed while retaining an intact
immune system, it has been shown recently that removing the FAP-positive
cells from a mouse can make the tumor vulnerable to vaccine-stimulated
immune attack. 133
These studies show the feasibility and variety of approaches in targeting the
unique proteolytic activity and expression pattern of FAP, which is expressed
in human tumors and fibrosis. It must be remembered, however, that FAP is
likely to have extra-enzymatic functions, owing to its potential ligand-binding
functions. The inhibitors described above target only the enzymatic activity,
thus allowing FAP to continue interacting with its binding partners. There
remains a need to develop FAP-selective inhibitors and substrates to distin-
guish FAP from similar enzymes including DPP-4 and PEP, thus providing a
better insight into the unique role of FAP in a wide range of disease states.
5.4 Recent Developments in the DPP-4 Protease
Significant advances in understanding the DPP-4 family of proteins can lead to
new therapeutic approaches that target these important enzymes. A novel role
for DPP-9 in regulating cell survival and proliferation via modulating mole-
cular signaling cascades has recently been reported. 164 Akt (protein kinase B)
activation was found to be significantly inhibited by over-expression of DPP-9
in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney
cells (HEK 293T). 164 Interestingly, the inhibitory effect of DPP-9 on Akt
pathway activation was growth-factor-dependent. DPP-9 over-expression
caused apoptosis and significantly less epidermal growth factor (EGF)-medi-
ated Akt activation. The effect of DPP-9 on Akt signaling did not occur when
DPP-9 enzyme activity was ablated by either active site mutagenesis or inhi-
bition. These findings suggest an important signaling role for DPP-9 in the
regulation of the EGF-dependent survival and proliferation pathways.
Discovery of the regulatory role of DPP-9 in EGF-mediated mitogenic effects
offers novel therapeutic implications. Hyperactivation of EGF signaling has
been attributed to various cancers, including breast, brain, colon, lung, and
prostate cancers. 165 Therefore, enhancement of DPP-9 enzyme activity, and
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