Improving outcomes for pancreatic ductal adenocarcinoma (PDAC) is critical, as current therapies offer limited benefits for most patients. The urokinase plasminogen activator (uPA) system is a key driver of cancer invasion and metastasis and thus anti-cancer target. The therapeutic potential of novel small molecule selective uPA-selective inhibitor, BB2-30F was evaluated in clinically relevant metastatic PDAC models.
Xenograft and immunocompetent orthotopic mouse models were created by co-implanting human AsPC-1 cells with cancer-associated human pancreatic stellate cells (PSCs) or KPC cells with murine PSCs in immune-deficient BALB/C nude or syngeneic C57BL/6 mice. In vitro, co-cultures were used to directly study the effect of BB2-30F on cancer cell-PSC cross-talk impacting cell proliferation, migration, apoptosis, signalling pathways, and tumour spheroid growth kinetics.
Using the uPA inhibitor BB2-30F alone or in combination with gemcitabine significantly reduced primary tumor growth, and decreased epithelial-mesenchymal transition, stemness, and infiltration by helper T cells and M2 macrophages, while enhancing cytotoxic T-cell infiltration in tumors. Crucially, this combination eliminated visible distant metastasis. BB2-30F counteracted the cancer promoting effects of PSCs in vitro.
In conclusion, our findings highlight the important role of uPA in PDAC progression involving the disruption of PSC-cancer cell crosstalk and supports uPA-targeted therapies as promising strategies for improving PDAC patient outcomes.