Novel Pathogenic Roles and Mechanisms of Fibrinogen in Pancreatic Cancer

The dismal prognosis associated with pancreatic ductal adenocarcinoma (PDAC) is attributed to the aggressive nature of these tumors and the lack of effective screening or treatment strategies. PDAC is especially problematic for the U.S. Veterans population, which has a higher PDAC prevalence than the general population. Studies have shown that patients with PDAC have a high rate of venous thromboembolism (VTE), which is also an important cancer-associated factor in the Veteran population. Critically, patients with VTE are more likely to have an advanced stage of cancer and worse prognosis than patients without VTE. Fibrinogen is primarily considered in the context of hemostasis; however, it is also important for other processes such as cell-cell interaction, inflammation, and tumorigenesis. Although fibrinogen levels are elevated in cancer patient plasma and cancer tissues, the mechanistic roles for fibrinogen in the pathogenesis of any cancer, including PDAC, are largely unknown. We have performed extensive preliminary studies to show functional roles of fibrinogen in PDAC. For the current project, we hypothesize that increased fibrinogen expression in the basal subtype of PDAC plays an important role in cancer progression through the AKT/STAT3 signaling axis, thereby promoting EMT/metastasis, chemoresistance and anti-apoptosis in cancer cells. We propose that a novel therapy (A2 protein) targeting fibrinogen in combination with the first-line chemotherapeutic drug regimen (FOLFIRINOX) could be beneficial primarily for PDAC patients with basal subtype tumors. Two specific aims are proposed: 1). Determine the functions and molecular mechanisms of tumor-derived fibrinogen in the pathogenesis of the basal subtype of PDAC in vitro and in vivo. 2). Determine the therapeutic efficacy of the novel combination of chemotherapy with A2 protein targeting fibrinogen in the basal subtype of PDAC in PDX mouse models. The proposed project is highly relevant to U.S. veterans due to their increased risk for PDAC. With the in depth research on roles of tumor-derived and systemic fibrinogen on PDAC progression, and effective targeting strategy, we expect this project to offer a new, groundbreaking paradigm for VA patient care, and bring a novel treatment option for basal subtype of PDAC patients. Results obtained from the current project will be ready to implement into clinical trials.