Heparan sulfate proteoglycans (HSPGs) are primary components at the interface between virtually every eukaryotic cell and its extracellular matrix (ECM). HSPGs not only provide a storage depot for heparin-binding molecules in the cell microenvironment, but also decisively regulate their accessibility, function and mode of action. As such, they are intimately involved in modulating cell invasion and signaling loops that are critical for tumor growth. In a series of studies performed since the cloning of the human heparanase gene we and others have demonstrated that heparanase, the sole heparan sulfate (HS) degrading endoglycosidase, is causally involved in cancer progression and hence is a valid target for drug development. We have generated a novel chemically modified non-anticoagulant heparin (termed *SST0001) that potently inhibits heparanase enzymatic activity and tumor growth and metastasis in xenograft cancer models (i.e., multiple myeloma, pancreatic carcinoma, Ewing's sarcoma, glioma). Compound SST0001 is being subjected to phase I/II clinical trial in myeloma patients. Building on the premise of this lead compound, we are currently developing second generation oligosaccharide-based heparanase-inhibiting compounds that exhibit therapeutic along with pharmacological properties that will further advance translation of this therapy to the clinic. Given the increasing significance of neutralizing monoclonal antibodies (mAb) in the treatment of human diseases, we have generated heparanase neutralizing mAb directed against the substrate binding domain of heparanase. These antibodies are being tested in preclinical cancer models. Newly resolved structural features of the heparanase protein provide a strong basis for an ongoing rational design of heparanase inhibitors, including small molecules.
*SST0001 is a property of Sigma-Tau Research Switzerland S.A.
