Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with an average 5-year survival rate of 9%1. A major hallmark of PDAC is the dense, collagen-rich stroma that is present in and around the tumour. This collagen rich tumour microenvironment leads to poor penetration of chemotherapy and gives cancer cells a route to metastasise.
In the extracellular matrix, a critical player in collagen synthesis is a class of copper-dependent enzymes called the lysyl oxidases (LOXes). The expression of the LOX family is significantly associated with poor patient survival in pancreatic cancer. Targeting this class of enzyme may well attenuate the metastatic potential for PDAC, improve chemotherapy efficacy and subsequently result in a better clinical outcome.
LOXes absolutely require incorporation of copper into their catalytic domain for activity. Copper chelators such as ammonium tetrathiomolybdate (ATTM), has received rising attention in cancer therapeutics leading to a Phase II breast cancer clinical trial2. ATTM is clinically approved for Wilson’s disease and is well-tolerated by patients. To date, ATTM has not been investigated in PDAC.
Using our amplex red coupled kinetics assay, we found that ATTM inhibits LOX activity in pancreatic cancer cells and cancer-associated fibroblasts. In 3D organotypic matrix assays, we have shown that ATTM can reduce collagen remodelling leading to a softer matrix as measured by unconfined compression testing. Moreover, ATTM has significantly reduced cancer cell invasion in these collagen matrices. Taken together these data, LOXes can be inhibited via their copper binding domains in vitro, leading to changes in fibrillar collagens deposited in the extracellular space, and warrant further investigation in vivo to understand their potential as an anti-stromal therapy.