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BCRF Grantee Since

1996

Donor Recognition

The Estée Lauder Award

Area(s) of Focus

H. Shelton Earp, MD

Professor and Director, UNC Cancer Care
Lineberger Comprehensive Cancer Center
University of North Carolina
Chapel Hill, North Carolina

Current Research

The UNC Lineberger team led by Dr. Earp continues its research program featuring clinical and genetic breast cancer research centered on the EGF receptor and other receptor tyrosine kinase families. This report relays recent progress and budget expenditures for the three areas:

  • Improved Anti-HER2 Breast Cancer Vaccine Strategies
  • EGF Receptor Family in Breast Cancer: the Role of HER4 and WWOX
  • Mer Receptor Tyrosine Kinase – Role in Breast Cancer Tumor-Associated Macrophages and Triple Negative Breast Cancer

The Phase I/II HER2 vaccine trial— investigating the combination of vinorelbine, trastuzumab and a multi-HER2 epitope dendritic cell vaccine in the treatment of women with high HER2-expressing metastatic breast cancer—has completed accrual and will be in analysis over the next 12 months. The first three EGFR family members (EGFR, HER2 and HER3) are associated with poor breast cancer prognosis while HER4 can be a good prognostic sign. Investigating the HER4 mechanisms led Dr. Earp’s team to WWOX, a tumor suppressor of unknown function that binds HER4. Some human breast cancers lose WWOX expression and, due to a genomic aberration, some breast cancers express a truncated WWOX protein. The team’s experiments confirm that WWOX suppresses breast cell growth and show for the first time that expressing the truncated WWOX stimulates breast cancer cell growth. Lastly, their lab identified another receptor tyrosine kinase, Mer, which is overexpressed in triple negative breast cancer cell lines. MDA-231 cells that more frequently metastasize to the brain in pre-clinical models express even higher Mer levels. In addition, Mer’s normal function in tumor macrophages may play a role in breast cancer progression by suppressing the immune response to tumors. Dr. Earp’s initial data (Journal of Clinical Investigation, in press) demonstrate that Mer signaling helps create the immune suppression produced by tumor-associated macrophages. Elimination of Mer signaling allows the immune system to fight mammary tumors in pre-clinical models. These studies aim to open new avenues of breast cancer immune therapy.

In 2013-2014, Dr. Earp’s team will finalize and publish their Breast Cancer Vaccine Trial results, investigate the oncogenic and tumor suppressive function of HER4 and WWOX, and study the breast cancer microenvironment role of the Mer receptor tyrosine kinase, as well as test whether inhibition of Mer will stimulate anti-breast cancer immunity.

Mid-Year Summary

The Phase I/II HER2 vaccine trial, investigating the combination of vinorelbine, trastuzumab and a multi-HER2 epitope dendritic cell vaccine in the treatment of women with HER2 positive metastatic breast cancer, is finished accruing and will be in analysis over the next 12 months. One clinical publication and one vaccine correlative science publication emphasizing the DNA sequence of vaccine responsive T cells are planned. The combined vaccine strategy produced a specific immune response in a subset of patients; a specific immune response, when detected, correlated with improved survival.

The first three EGFR family members (EGFR, HER2 and HER3) are associated with poor breast cancer prognosis while HER4 can be a good prognostic sign. Investigating the HER4 mechanisms led Dr. Earp’s team to WWOX, a tumor suppressor of unknown function that binds HER4. Some human breast cancers lose WWOX expression and, due to a genomic aberration, some breast cancers express a truncated WWOX protein, termed WWOX. The Earp team’s experiments confirm that WWOX suppresses breast cell growth and shows that expressing the truncated WWOX stimulates breast cancer cell growth and invasive behavior.

Lastly, the Earp lab identified another receptor tyrosine kinase, Mer, whose normal function is to trigger clearance of apoptotic cells and debris Mer signaling polarizes tumor macrophages towards an anti-inflammatory, wound-healing M2-phenotype. This plays a role in breast cancer progression by suppressing the immune response to tumors. The researchers’ initial data (J Clin Invest. 2013 Oct;123(10):4329-4343. PMCID:PMC3784526) demonstrated that Mer signaling helps create the immune produced by tumor-associated macrophages. Genetic deletion of Mer signaling allows the immune system to fight mammary tumors in pre-clinical models. A Mer tyrosine kinase small molecule inhibitor is being developed at UNC and is being tested as an immune-therapeutic agent in pre-clinical models of mammary cancer.

Bio

Dr. H. Shelton Earp is a graduate of the University of North Carolina School of Medicine. After a medical internship at Vanderbilt and service in the army, he returned to Chapel Hill where he performed his residency and fellowship, joining the faculty in 1976. He is now the Lineberger Professor of Cancer Research and a professor in the Departments of Medicine and Pharmacology. In his role as Director at the UNC Lineberger Comprehensive Cancer Center, he coordinates cancer research and care at one of the country's premier public universities, including establishment of cancer epidemiology and prevention research programs with faculty in the School of Public Health.

Dr. Earp’s laboratory conducts clinical and translational breast cancer research as well as basic research on the behavior of cancer cells by studying the signals that regulate cell growth, differentiation and programmed cell death. His group has identified and studied genes involved in these cellular decisions. He has authored 160 biomedical-research papers. He serves as Principal Investigator of the UNC Breast Cancer SPORE and UNC Lineberger Comprehensive Cancer Center grants. The UNC Breast SPORE, one of the original four Breast Cancer SPOREs, was just renewed for five years, Years 15-19.

Dr. Earp has been the recipient of UNC School of Medicine teaching awards and has served on boards and chaired national review committees for the American Cancer Society and the National Cancer Institute. He is an elected member of the American Association of Professors, the American Society of Clinical Investigation, and recently served as President of the American Association of Cancer Institutes.

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