More than a gel - Hyaluronic acid, a central component in the microenvironment of pancreatic cancer

Hyaluronic acid or hyaluronan (HA) is a major stromal component and its accumulation has been shown to play a central role in promoting tumourigenesis and progression of disease. Thus, overexpression of HA in tumours is associated with poor prognosis. Therapeutic targeting of HA is therefore an attractive strategy, particularly in pancreatic ductal adenocarcinoma (PDA), which is associated with an extremely poor prognosis and less sensitivity towards chemotherapy. PDA is characterised by a high stromal content. The accumulation of dense, fibrotic extracellular matrix components within the stroma, termed desmoplasia, results in increased tumour interstitial fluid pressure and vascular compression that impair the delivery and efficacy of therapeutic agents. While some elements of the stroma may be protective for the patient and prevent a more aggressive phenotype of PDA, a pegylated recombinant human hyaluronidase (pegvorhyaluronidase alfa) has been found to inhibit tumour growth in preclinical studies. In a clinical phase II randomised trial, the addition of pegvorhyaluronidase alfa to nab-paclitaxel and gemcitabine suggested significantly longer progression-free survival in patients with advanced PDA compared with nab-paclitaxel and gemcitabine alone. This benefit was even more pronounced in a subgroup of patients who expressed high levels of tumour HA.