2020 Grant Recipient Jill Smith, MD

2020 & 2022 Grantee: Jill Smith, MD

Georgetown University
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
Amount: $500,000

Award Extension: 2022 Pancreatic Cancer Action Network Translational Research Grant Extension funded by Kenneth D. Custance and Gladys C. Custance, honoring the memory of Martha ‘Molly’ Reed Woodroofe
Award Period: July 1, 2022 – June 30, 2023
Amount: $250,000

Jill Smith, MD

Biographical Highlights

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.

Project Overview

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.

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.

Project Overview: 2022 Extension

Dr. Smith’s research team has identified the cholecystokinin-B receptor (CCK-BR) – a special class of protein – as a novel target for the treatment of pancreatic cancer. They have shown that the KRAS mutation – a genetic mutation that’s present in nearly all pancreatic tumors – leads to CCK-BRs becoming over-expressed in the pancreas. Activation of 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). With funding from her 2020 PanCAN Translational Research Grant, Dr. Smith and her team sought to develop proglumide as an addition to standard chemotherapy to improve drug uptake (i.e., the drug’s ability to penetrate the tumor) and treatment response in pancreatic cancer.

Based on the project’s promising results to date, the Smith lab received FDA approval to perform a clinical trial for the addition of proglumide to standard of care treatment in patients with advanced pancreatic cancer. In addition, Dr. Smith has been awarded a one-year extension of her PanCAN Translational Research Grant to achieve the following objectives:

Explore the role of the novel targets that they identified through genetic sequencing tests. They found some genes either up- or down-regulated in response to proglumide treatment. These targets could hold promise for future pancreatic cancer therapies alone or in combination with proglumide.
Further investigate the mechanisms by which proglumide halts stellate cell migration and activation and disrupts the formation of fibrosis. The Smith lab has obtained human pancreatic stellate cells to conduct these experiments in a model most closely related to human disease.
Look for and validate biomarkers – measurable biological clues – in blood samples from mice and patients treated with gemcitabine with or without proglumide. One of the types of biomarkers they’re analyzing are small pieces of genetic material called microRNAs. Preliminary evidence suggests that the levels of certain microRNAs are impacted by proglumide treatment, and their presence could signify whether the patient is likely to respond to this treatment approach.

Overall, this additional funding will allow Dr. Smith and her team to further understand, refine and improve their investigational treatment option and prepare to translate this strategy to potential human benefit.