Cascia
LOX Propeptide

When the mature lysyl oxidase enzyme is expressed into the extracellular space, it undergoes post-translational processing as more fully descripted in the page about the LOX inhibitor candidate.  Following processing and proteolytic cleavage, the LOX propeptide sequence is separated from the active enzyme.

It is known that the enzyme itself and the propeptide sequence have different biological actions, the range of which are only now starting to be researched.  At least seventeen different binding partners have been identified for the propeptide sequence, and the resultant biological effects of these different bindings are yet to be fully understood.

One interaction that has been well-documented is the ability of the LOX-PP to block binding of fibroblast growth factor 2 (FGF-2) with its receptor.  It is known that this blocking reduces the invasiveness of some cancer cells, a phenomenon that has been studied mainly in prostate cancer.  The suggested mechanism of inhibition is illustrated in the diagram on the right.  It is likewise known that the presence of LOX itself is up-regulated in some cancers, which suggests that when the pro-invasive actions of LOX are balanced by the anti-invasive actions of the LOX-PP, cells do not undergo transformation to a cancerous phenotype and the cancerous cells do not spread.  If the balance is not maintained, then cancer cells can become more highly invasive and the cancer can metastacize.

Cascia will study whether a recombinant protein version of the propeptide has the ability to restore this balance and to reduce the ability of cancer cells to spread.  This exact behavior has been reported in the scientific literature using colonies of cultured cells, but further study in animal models is warranted.  Likewise, it has been demonstrated that when a purified form of the LOX-PP was administered to animals being treated either for both breast or pancreatic cancer with doxorubicin, a commonly used chemotherapeutic agent, the cytotoxic effect of doxorubicin was significantly enhanced.

 A further potential use for this drug is to inhibit angiogenesis, the formation of blood vessels.  Angiogenesis is a normal function of human physiology, but when it become dysregulated it contributes to disease.  This occurs in often in cancers as the new blood vessels support growth of the tumor, but aberrant growth occurs in vascular diseases, rheumatoid arthritis, proliferative retinopathy, and other conditions with exuberant angiogenesis.