H. Shelton Earp, MD
Chapel Hill, North Carolina
Lineberger Professor of Cancer Research
Director, UNC Cancer Care
Professor of Medicine & Pharmacology
Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.
Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp's team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents. His team is identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.
Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response. To determine how MerTk and Tyro3 exert their influence, Dr. Earp and his collaborators developed laboratory models that recapitulate triple-negative breast cancer. In the last year, these models allowed his team to demonstrate that decreasing MerTK or Tyro3 dramatically increases the ability of immune cells to attack tumors.
The team will continue to build on their previous discoveries and assess the mechanism by which the absence of MerTK or Tyro3 mediates immune function against tumor cells. They will employ several techniques to examine the RNA expression in various immune cells of the tumor microenvironment and assess the spatial relationship between these immune cells and breast tumor cells. They will also continue to test previously developed small molecule MerTk inhibitors alone and in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these small molecule drugs can indeed improve immunotherapy. The results of these studies have the potential to unveil new ways to improve the efficacy of T-cell directed therapies so that more patients may benefit from immunotherapy, particularly TNBC patients that have few therapeutic options.
H. Shelton Earp, MD is the Lineberger Professor of Cancer Research, Director of UNC Cancer Care and Director of the UNC Lineberger Comprehensive Cancer. In these roles, he has helped develop basic, clinical and public health research and cancer care at one of the country’s premier public universities and academic medical centers. He serves as Principal Investigator of the UNC Breast Cancer SPORE and his laboratory conducts fundamental and translational research in breast cancer and childhood leukemia. His group has discovered and studied genes involved in a range of cancers, published over 200 biomedical-research articles and been continuously funded by NIH for over 40 years. He is currently collaborating with the UNC Chemical Biology Center in the Eshelman School of Pharmacy to develop a new, first-in-class drug targeting one of the cancer genes discovered in his lab. Inhibition of this gene may stimulate a breast cancer patient’s innate immunity against their cancer.
Dr. Earp has received UNC School of Medicine teaching awards and chaired national review committees for the American Cancer Society and the National Cancer Institute. He has served as President of the American Association of Cancer Institutes, on the NCI Board of Scientific Advisors, and on the advisory boards of ten university cancer centers. His lab is supported by NIH grants, the Breast SPORE and the Breast Cancer Research Foundation.
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