Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and metastatic tumour with poor prognosis. It is estimated to become the second most prevalent cancer by 2030 representing a significant burden of disease and complex therapeutic challenge.
PDAC is characterised by extensive extracellular matrix (ECM) remodelling leading to significant changes in both the biochemical and biomechanical properties of the tissue. In particular, PDAC typically presents with excessive deposition of fibrillar collagens in and around the tumour. This fibrosis contributes in part to the poor penetration of stand-of-care chemotherapies leading to the emergence of chemoresistance.
The lysyl oxidases (LOX) family of 5 enzymes are absolutely essential for the synthesis of collagen fibres. The LOX family are typically dysregulated in fibrotic diseases and cancers. To date, a functional role for lysyl oxidases has been reported in almost all solid tumours. High LOX family expression signatures are particularly associated with PDAC and represent a critical mediator of the desmoplastic response in these tumours. Therefore therapeutic targeting the LOX family is an exciting and emerging area of research.
We have recently completed the pre-clinical evaluation of a novel pan-LOX family inhibitor, PXS-5505 that specifically targets the LOX family of enzymes. We show PXS-5505 inhibits LOX family activity in our PDAC in vitro and in vivo models. Specifically, PXS-5505 results in fewer collagen cross-links in our models. In our in vivo genetically engineered mouse models of pancreatic cancer, PXS-5505 extends survival when used in combination with standard-of-care chemotherapy versus chemotherapy alone. Overall, we show our anti-stromal targeting strategy is able to increase efficacy of standard-of-care chemotherapy by targeting the underlying mechanism of tumour fibrosis.