The potential of heparanase as a therapeutic target in cancer

Abstract

Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization.

Keywords: Antitumor therapy; Drug target; Heparanase; Heparanase inhibitors.

Figure 1. Scheme showing the effects of heparanase (Hpa) involving tumor/microenviroment interactions

1) cleavage of heparan sulfate (HS) by heparanase (as indicated by the solid arrows) and release of heparan sulfate-bound growth factors (GF) from proteoglycans; 2) growth factor-mediated signaling; 3) proangiogenic signaling; 4) disassembly of extracellular matrix and release of HS-bound growth factors.

Figure 2. Structures of selected heparanase inhibitors

A. Schematic representation of SST-0001 and chemical modification characterizing the heparin derivative. Given the polymeric nature of SST-0001 (average molecular weight, 20 kDa) a "statistical" representation of the structure is shown. B. Schematic representation of M402 (average molecular weight, 6 kDa). As for SST-0001, a "statistical" representation of the structure is shown. R=SO₃ or Ac.

Figure 3. Structures of heparan sulfate mimetics

A. Structure of the heparan sulfate mimetic, PG545, a fully sulfated oligosaccharide conjugated with a lipophilic moiety. B. Structure of PI-88, a mixture of sulfated di- to hexasaccharides. C. Structure of maltohexaose sulfate.