Heparanase: a target for drug discovery in cancer and inflammation

Abstract

The remodelling of the extracellular matrix (ECM) has been shown to be highly upregulated in cancer and inflammation and is critically linked to the processes of invasion and metastasis. One of the key enzymes involved in specifically degrading the heparan sulphate (HS) component of the ECM is the endo-b-glucuronidase enzyme heparanase. Processing of HS by heparanase releases both a host of bioactive growth factors anchored within the mesh of the ECM as well as defined fragments of HS capable of promoting cellular proliferation. 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. So far only one compound, the sulphated oligosaccharide PI88, which both inhibits heparanase activity and has effects on growth factor binding has reached clinical trials where it has shown to have promising efficacy. The scene has clearly been set however for a new generation of compounds, either specific to the enzyme or with dual roles, to emerge from the lab and enter the clinic. The aim of this review is to describe the current drug discovery status of small molecule, sugar and neutralising antibody inhibitors of heparanase enzyme activity. Potential strategies will also be discussed on the selection of suitable biomarker strategies for specific monitoring of in vivo heparanase inhibition which will be crucial for both animal model and clinical trial testing.

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

“…Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9)(10)(11)(12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).…”

Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo

“…Therefore, heparanase may facilitate tumor cell invasion and neovascularization, which are critical steps in cancer metastasis. Since the heparanase gene was cloned by four independent groups (3-6), a large number of studies have clearly linked heparanase expression to the process of tumorigenesis and invasion in a wide number of cancers, including gastric, liver, colon, pancreatic, esophageal, breast, bladder, prostate, brain, thyroid, ovary, lung, and acute myeloid leukemia (11). The overexpression of the heparanase cDNA in tumor cells with a low metastatic ability conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality (6).…”

Genomic studies of GVHD—lessons learned thus far

“…39,40 Its role in cancer metastasis has been well elucidated 41 , and evidence indicates its involvement in inflammation and autoimmunity. 42 A large-cohort study using unrelated HLA-matched donor --recipient pairs discovered a highly significant correlation between HPSE SNPs and both aGVHD and extensive cGVHD. 15 While the mechanisms behind aGVHD have been well elucidated, cGVHD pathogenesis remains poorly understood.…”