GRANTEE: David Linehan, MD
University of Rochester
Research Project: Targeting Inflammatory Monocytes in Metastatic Pancreas Cancer
Award: 2015 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2015 – June 30, 2017
Dr. Linehan graduated from the University of Massachusetts Medical School before fulfilling his internship and residency at Deaconess-Harvard Surgical Service. He completed a research fellowship at Brigham and Women’s Hospital before he became chief resident in surgery at Beth Israel Deaconess Medical Center. Dr. Linehan finished his medical training as the Kristin Ann Carr Fellow in Surgical Oncology at New York’s Memorial Sloan-Kettering Cancer Center. He currently serves as chair of the department of surgery at Rochester University, where he holds the Seymour I. Schwartz Professorship in Surgery.
A cancer surgeon, Dr. Linehan specializes in treating cancers of the liver, pancreas and gastric and biliary tract. He has been recognized for bringing innovative therapies to patients with hard-to-treat cancers.
Pancreatic tumors are made up of a complex mixture of cells, including both cancerous and noncancerous cells. When the tumor forms, various cell types are recruited to the site of the tumor and promote cancer progression. A large portion of the non-tumor cells are called “inflammatory monocytes” (IMs). Dr. Linehan and his colleagues have found that high levels of IMs in pancreatic cancer patients’ blood correlates with poor survival.
Dr. Linehan’s proposed project involves blocking the recruitment of IMs to the site of the tumor using a drug called a CCR2 inhibitor (CCR2i). CCR2 is a receptor, or protein on the cell surface, that binds to particular chemokines. Chemokines are small proteins that are released from cells in order to activate other cells to migrate, or move, to a different place. In this case, blocking CCR2 prevents IMs from migrating from the bone marrow to the site of the tumor. Dr. Linehan and his colleagues have conducted a Phase Ib clinical trial, testing CCR2i in combination with standard chemotherapy in patients with locally-advanced pancreatic cancer. Preliminary results show a significant decrease of IMs in primary tumors, leading to a nearly double response rate in comparison to chemotherapy alone.
For this project, Dr. Linehan will conduct further experiments using the CCR2i in mouse models of pancreatic cancer. He and his research team will test whether CCR2i is effective in mice with metastatic disease, as compared to the early results in patients with localized tumors. Further, experiments will test the administration of CCR2i with different drugs, to identify the most effective combination and the optimal timing of treatment. The results of the proposed project will assist in the design of future clinical trials utilizing CCR2 blockade to improve outcomes for pancreatic cancer patients.