Discovery of Well Defined Sulfated Glycopolymers as Specific Heparanase Inhibitors for Cancer Therapeutics

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The remodeling of the extracellular matrix has been shown to be highly upregulated in cancer and inflammation and is critically linked to the processes of invasion and metastasis.  The finding that heparanase is elevated in a wide variety of tumor types and is subsequently linked to the development of pathological processes has led to an explosion of therapeutic strategies to inhibit its enzyme activity.  Heparanase is a heparin sulfate polysaccharide degrading endoglycosidase enzyme that is being targeted in cancer patient clinical trials.  This strategy is supported by the fact that heparanase is present in high levels across all cancer types and has been correlated with increased tumor size, angiogenic activity, enhanced metastasis, and overall poor patient prognosis.  However, the current carbohydrate-based heparinase inhibitors are heterogenous in size and sulfation pattern (the pattern serves as a heparin mimetic to block heparanase’s active site), which leads to nonspecific binding and unforeseen adverse events.  The clinical use of these inhibitors has currently been halted. 


The inventors have designed and synthesized a novel inhibitor consisting of a glycopolymer of 12 repeating units bearing a pendant saccharide unit that allows this inhibitor to bind heparanase tighter than previously utilized agents.  This synthetically designed glycopolymer also possesses minimal cross-bioreactivity to serine proteases in the coagulation cascade and several heparan sulfate binding proteins, which highlights an additional advantage this novel inhibitor has over previous heparanase inhibitors.  The off-target effects that were involved in the clinical failure of previous heparanase inhibitors included anticoagulant activity, which put patients at risk of bleeding complications.  The inventors have tested this novel inhibitor in a preclinical scenario, in which it demonstrated action against P-selectin (when combined with heparanase inhibition, provides a dual mechanism of action against cancer) and prevented metastasis in a 4T1 breast cancer mouse model.


Patent Information:
For Information, Contact:
Ken Massey
Wayne State University
Hein Nguyen
Ravi Loka
Eric Sletten
Israel Vlodavsky
Cancer Therapies