Pancreatic cancer is an aggressive malignancy marked by propensity for early metastatic spread and resistance to therapy. My research interests span basic science, translational and clinical research projects to improve our understanding of the pancreatic cancer pathobiology and improve outcomes for patients diagnosed with this disease. Broadly, our research focuses on the inflammatory and immune response to pancreatic cancer and its associated treatments. Specific research topics include: 1) the role of neutrophil extracellular traps (NETs) in the pathogenesis of pancreatic cancer and pancreatitis, 2) thromboinflammatory mechanisms of cancer associated hypercoagulability, 3) clinical trials evaluating the NET inhibitors in pancreatic disease, 4) the inflammatory response to surgery for resection of cancer and the impact on long term oncologic outcome, 5) minimally invasive approaches to pancreatic surgery, and 6) treatment response to neoadjuvant therapy for pancreatic cancer.
Neutrophil extracellular traps (NETs) occur when activated neutrophils expel their intracellular contents including DNA, histones, granules and other components into the extracellular space, tumor, or circulation. We have identified a critical role of NETs in pancreatic cancer progression and hypercoagulability. The components released from NETs promote pancreatic tumor microenvironment fibrosis which limits efficacy of treatment and prevents an effective immune response. NETs released in the circulation promote establishment of metastatic tumor deposits. NETs are also a critical component of the inflammatory and immune response to surgery in cancer patients, thus we are investigating how these responses impact long term cancer associated outcomes.
Pancreatic cancer is known to result in a hypercoagulable state with venous thromboembolism (VTE) affecting up to 40% of patients during their course of treatment. Furthermore, VTE is an independent predictor of worse survival in pancreatic cancer patients. The mechanisms promoting this pro-thrombotic state are poorly understood. Our work has shown that NETs promote hypercoagulability in pancreatic cancer. We are currently evaluating strategies to reverse cancer associated hypercoagulability and limit VTE by targeting NETs.
Development of effective clinical strategies requires translation of laboratory findings to the bedside in the form of early phase clinical trials of novel agents. We have previously studied the autophagy and NET inhibitor hydroxychloroquine (HCQ) as a neoadjuvant treatment in pancreatic cancer patients, demonstrating safety and tolerability of HCQ when combined with chemotherapy, followed by a randomized trial to evaluate treatment response. Our future studies will focus on additional targets for NET inhibition as novel neoadjuvant treatments, as well as evaluating NET inhibition as a thromboprophylaxis strategy in the perioperative setting for patients undergoing pancreatic resection.
My clinical outcomes research evaluates strategies to improve care of patients with pancreatic cancer. This includes evaluating treatment outcomes related to the utilization of minimally invasive approaches to surgical resection, the use of neoadjuvant treatments and biomarkers of treatment response to facilitate surgical decision making.
