2020 Grantee: Jill Smith, MD
Research Project: Proglumide and the Pancreatic Cancer Microenvironment
Award: 2020 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2020 – June 30, 2022
Dr. Jill P. Smith is a clinician scientist and professor of medicine at Georgetown University and a member of the Lombardi Comprehensive Cancer Center. She also is a staff physician in gastroenterology and hepatology at the DC Veterans Affairs Medical Center.
Her passion has always been bench-to-bedside, or translational, research. She was recruited to Georgetown University from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, to establish a translational research program in gastrointestinal cancer.
Her basic science research for over two decades has focused on cholecystokinin receptors and other G-protein coupled receptors, which are proteins that sit on the surface of a cell and transmit signals from outside to inside the cell. Her research focuses on pancreatic cancer and hepatocellular carcinoma in understanding the mechanisms involved with carcinogenesis (what makes cancer form) and developing novel strategies for therapy or cancer prevention.
In this Pancreatic Cancer Action Network Translational Research Grant project, Dr. Smith’s team will study the effects of a drug, proglumide, and its actions to render pancreatic cancer more responsive to therapy. Pancreatic cancer typically responds poorly to therapy. Reasons for the poor response include the lack of target-specific therapies as well as the dense fibrosis in the tumor microenvironment. This fibrosis can impede the penetration of chemotherapy as well as cell-killing immune T-cells into the tumor.
Dr. Smith’s research team has identified the cholecystokinin-B receptor (CCK-BR) as a novel target for the treatment of pancreatic cancer. They have shown that CCK-BRs become over-expressed in the pancreas under the influence of the KRAS mutation that is present in nearly all pancreatic tumors. Activation of the CCK-BR stimulates growth of pancreatic cancer cells in culture (grown in the lab) and tumors in animal models.
Furthermore, CCK-BRs are also expressed on pancreatic stellate cells – one of the cell types in the pancreas responsible for the dense fibrosis in the tumor microenvironment. The team has strong evidence that treatment with proglumide, a drug that acts as a CCK receptor antagonist (inhibitor), decreases fibrosis in the pancreatic tumor microenvironment and increases the influx of killer immune T-cells to the tumor.
Proglumide is an older drug that was originally developed 30 years ago for peptic ulcer disease but is no longer used for that indication since the development of more potent proton pump inhibitors. However, proglumide has been tested in over 600 human subjects, where it was found to be safe and without toxicity (side effects).
The investigators’ goal is to develop proglumide as an addition to standard chemotherapy in order to improve drug uptake and response in pancreatic cancer. In the first aim of this study, they will examine the effects of combination therapy with proglumide and gemcitabine chemotherapy on survival and the tumor microenvironment of mice bearing pancreatic cancers. In the second aim, Dr. Smith and team will focus on the mechanisms involved in the activation of this CCK-BR signaling pathway in the pancreatic microenvironment, especially in regard to fibrosis and immune cells.