By 2030, pancreatic cancer is projected to become the second most common cause of cancer-related death. Pancreatic ductal adenocarcinoma (PDAC) comprises over 90% of all cases of pancreatic cancer. The major hallmark of this disease is the dense, collagen-rich stroma that presents within and encapsulates the tumour, hindering the penetration of systemic chemotherapy and providing a route for cancer cells to metastasize. Chemotherapy remains the mainstay of treatment for PDAC patients and whilst initially effective at killing cancer cells, it elicits a wound healing response that exacerbates the fibrosis and subsequently resistance against the treatment. Novel approaches targeting this fibrosis will likely enhance the efficacy of current standard-of-care chemotherapy.
Recently, studies have proposed the use of copper depletion therapy in cancer treatment as excess copper has been linked with cancer progression and metastasis. Copper is critical to cell survival as it is incorporated as a cofactor in fundamental biochemical processes including cell growth, mitochondrial respiration, and extracellular matrix formation. Emerging evidence has demonstrated that inhibiting copper uptake in cancers can potentially overcome current challenges in drug resistance by targeting multiple pathways simultaneously. Copper chelators such as Ammonium tetrathiomolybdate (ATTM) are already approved for use in the copper accumulation disease, Wilson’s disease, and are under investigation in other forms of cancer, however to date, they have not been investigated in PDAC.
Our data shows that ATTM inhibits lysyl oxidase (LOX) activity in pancreatic cancer cells and cancer-associated fibroblasts. The LOX family is a group of copper-dependent enzymes that underpins tissue and tumour fibrosis through collagen crosslinking. Additionally, ATTM significantly reduces the metabolic activities of both cell types via inhibiting key intracellular cuproenzymes. In 3D organotypic matrix co-culture models, depleting copper with ATTM reduces cancer cell invasion. Furthermore, when used in combination with chemotherapy in orthotopic in vivo models of PDAC, it significantly extends survival and reduces metastasis compared to chemotherapy alone. These findings support further investigation into the targeting of copper-dependent metalloenzymes in combination with chemotherapy in difficult-to-treat solid tumours such as PDAC.