Heparan sulfate (HS) is a carbohydrate of varied structure that attaches to proteins found on the cell surface and in the extracellular matrix. Emerging evidence indicates that this process is deregulated in cancer and affects cancer cell interactions with the tumour microenvironment and the immune system, promoting cancer progression and metastasis. Funded by the Marie Skłodowska-Curie Actions programme, the HEPINIB project proposes to use as a drug target the enzyme heparanase that cleaves HS and contributes to the remodelling of the extracellular matrix. The working hypothesis is that the therapeutic targeting of heparanase will work on many levels, impeding metastasis, angiogenesis and inflammation.
Cancer is a leading cause of mortality within the aging European population. Therapeutic targeting is hampered by the complexity of the disease, which includes not only molecular changes within the tumor cell itself, but also within its microenvironment. Tumor angiogenesis, tumor-stroma interactions, interactions with immune cells, with the extracellular matrix and cancer stem cell niches allow for malignant cell survival and promote metastasis, the leading cause for cancer-associated mortality. Proteins substituted with the heparin-related carbohydrate heparan sulfate (HS) are dysregulated in malignant diseases, and are known to modulate all of the aforementioned processes of tumor progression. Several functions of HS-PGs in tumor progression are modulated by the enzyme heparanase (HPSE), which is barely expressed in adults, but upregulated during tumor progression, inflammation and angiogenesis, thus constituting an excellent drug target. Indeed, HPSE, the sole HS degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis and inflammation. HPSE accomplishes this by degrading HS and thereby regulating the bioavailability of heparin-binding proteins, priming the tumor microenvironment and mediating tumor-host crosstalk. We predict that therapeutic targeting of HPSE to be superior to conventional approaches, as it does not only have the potential to synchronously targeting tumor progression and metastasis at multiple levels (metastasis, angiogenesis, inflammation & immunity), but it is also be expected to have a favourable side effects profile. HEPINIB will combine leading experts of HPSE-related cancer research with non-academic partners providing a panel of innovative technologies with the aims of providing a deeper understanding of HPSE function in tumor progression, of developing novel HPSE inhibitors and delivery systems, and of trans-sectoral and interdisciplinary training of young scientists.
