BLR&D Research Career Scientist Award Application

Michael E Debakey Va Medical Center, Houston TX

Investigators

Abstract

As the risk for pancreatic ductal adenocarcinoma (PDAC) has increased to a higher rate in veterans relative to that in the general population, there is an urgent need to better understand the mechanism of PDAC pathogenesis and resistance to treatment, and to develop effective therapies to treat PDAC for veterans in the VA system. My research focuses on pancreatic cancer pathogenesis and therapy, bringing in new additions to the research areas at Michael E. DeBakey VA Medical Center (MEDVAMC) Center for Translational Research on Inflammatory Diseases (CTRID) with the goal of enhancing the research environment at our local MEDVAMC. My research projects include investigating the pathogenic roles of mesothelin, microRNA-198, and fibrinogen in PDAC; novel virus-like particles (VLPs) based immunotherapy strategies for PDAC; epigenetic deconvolution (EDec) method to deconvolute complex tumor compositions and stratify PDAC subtypes for better immunotherapy efficacy. My research in understanding the significant roles of mesothelin (MSLN) and miR-198 in pancreatic cancer has resulted in several impactful publications. We proposed the new concept of a tumorigenic factor interactome connected through tumor suppressor microRNA-198 in PDAC which has garnered much attention and influenced novel therapeutics development. The promising pre- clinical data on MSLN-VLPs immunotherapy in PDAC is also very encouraging and warrants further translational investigation. To tackle the problem of resistance to immune checkpoint inhibitor immunotherapy, we utilized the EDec method, which revealed many possible mechanisms and subtypes of PDAC that could guide further therapeutics development. Furthermore, our recent study has indicated that fibrinogen is a pathogenic factor for PDAC and could be a novel biomarker for more aggressive PDAC subtype. During the RCS award period, I will further develop my research program with a unique focus on roles of hematological factors in PDAC. 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 and fibrin is the major component in blood clot. 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. Here, we will test our hypothesize that increased fibrinogen expression in the basal subtype (more aggressive) 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. Specifically, we will determine: 1). The functions and molecular mechanisms of tumor-derived fibrinogen in the pathogenesis of the basal subtype of PDAC in vitro and in vivo. 2). The therapeutic efficacy of the novel combination of chemotherapy with A2 protein targeting fibrinogen in the basal subtype of PDAC in PDX mouse models. These projects are highly relevant to US veterans with their higher risk for PDAC than that of the general population. Our findings may offer a new, groundbreaking paradigm for VA patient care. In addition, I will continue to further expand collaborations with scientists at local and national VA facilities by providing our collection of PDAC PDX models, to mentor and train VA young scientists in PDAC research, to participate in VA administrative services, to participate in national and international grants review study sessions, and to pursue cutting edge research to develop effective PDAC therapeutics and bring them to clinical practice.