Oral Presentation The Pancreas Summit 2025

Selective Urokinase Inhibition plus Chemotherapy: A Novel Approach to Pancreatic Cancer Treatment via Enhanced Anti-Tumour Immunity and Decreased Metastasis (125930)

S M Zahid Hosen 1 , Ashna Kumar 2 , Zhihong Xu 1 , Alpha Raj Mekapogu 3 , Chamini Perera 1 , Tony Pang 4 , Romano Pirola 1 , Jeremy Wilson 1 , David Goldstein 5 , Benjamin Buckley 2 , Michael J Kelso 2 , Marie Ranson 2 , Minoti Apte 1
  1. Pancreatic Research Group, Southwest Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW(AUS), Australia
  2. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW(AUS), Australia
  3. Cancer and Stem Cell Lab, Faculty of Medicine and Health, The University of Sydney, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW(AUS), Australia
  4. Westmead Clinical School, University of Sydney, Sydney, NSW(AUS), Australia
  5. Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW(AUS), Australia

Background and 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 BB2-30F’s therapeutic potential alone and with gemcitabine in metastatic pancreatic cancer models. Additionally, 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 BB2-30F’s effect (with or without gemcitabine) on cancer cell-PSC crosstalk impacting cell proliferation, migration, apoptosis, signalling pathways, and tumour spheroid growth kinetics.

Results: Using the uPA inhibitor BB2-30F alone or with gemcitabine significantly reduced primary tumour growth, and decreased epithelial-mesenchymal transition, stemness, and infiltration by helper T cells and M2 macrophages, while enhancing cytotoxic T-cell infiltration in tumours. Crucially, this combination eliminated visible distant metastasis.

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

Keywords: Urokinase Plasminogen Activator (uPA), Tumour Microenvironment (TME), Metastasis and Immune activation.