Selective Urokinase Inhibition Plus Chemotherapy: A Novel Approach to Pancreatic Cancer Treatment via Enhanced Antitumor Immunity and Decreased Metastasis

Abstract

Background & aims: 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 key in PDAC progression, driving invasion and metastasis and mediating interactions between pancreatic stellate cells (PSCs) and cancer cells. We previously developed BB2-30F, a potent uPA-selective inhibitor. This study evaluates the therapeutic potential of BB2-30F alone and with gemcitabine in metastatic pancreatic cancer models. In addition, we aim to clarify the mechanisms underlying these effects.

Methods: Xenograft and immunocompetent orthotopic mouse models were created by co-implanting human AsPC-1 cells with cancer-associated human 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 study the effect of BB2-30F (with or without gemcitabine) on cancer cell-PSC crosstalk impacting cell proliferation, migration, apoptosis, signaling pathways, and tumor spheroid growth kinetics.

Results: Using the uPA inhibitor BB2-30F alone or 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.

Conclusions: BB2-30F-based uPA-targeted therapy is innovative and effectively curtails local tumor growth and metastasis in PDAC mouse models, suggesting the potential to significantly improve patient outcomes. Our findings highlight the role of uPA in PDAC progression, supporting the targeting of uPA protease activity as a promising therapeutic approach for PDAC.

Keywords: Metastasis and Immune Activation; Tumor Microenvironment (TME); Urokinase Plasminogen Activator (uPA).