H. Shelton Earp, MD
2012-2013 BCRF Project:
(made possible by generous support from Estée Lauder)
Professor and Director, Lineberger Comprehensive Cancer Center
Professor of Medicine and Pharmacology
University of North Carolina, Chapel Hill, NC
The UNC Lineberger team led by Dr. Earp continues its research program featuring clinical and genetic breast cancer studies centered on the EGF receptor family. Their projects aim to improve anti-HER2 breast cancer vaccine strategies and elucidate the role of HER4 in breast cancer.
Dr. Earp's team will continue their phase I/II HER2 vaccine trial, which is investigating the combination of vinorelbine, trastuzumab and a multi-epitope dendritic cell vaccine in the treatment of women with high HER2-expressing metastatic breast cancer. Their new strategies to overcome the immune suppressive state of tumors have shown promise by increasing percentages of specific HER2 directed against lymphocytes, a form of white blood cells.
In the second project, the researchers are studying the fourth member of the EGF receptor family, HER4. The first three members, EGFR, HER2 and HER3, are associated with poor prognosis breast cancer. HER4, which can be expressed as two different genetic variants, can be associated with positive or negative prognosis. With BCRF funding, Dr. Earp's team has shown that one variant, Cyt1, causes breast cell differentiation and slows breast cancer cell growth. The other variant (Cyt2) has the opposite effect; it stimulates hyperplasia, or cell proliferation. The scientists are unraveling the mechanisms by which these HER4 isoforms act and are attempting to understand how they promote or suppress breast cancer formation. They are also beginning further studies of signaling from the EGF receptor family using a new technology to quantify a large proportion of the breast cancer cell's protein kinases following stimulation or inhibition of family members.
Mid-year Progress: The UNC Lineberger team continues its research program featuring clinical and genetic breast cancer research centered on the EGF receptor and other receptor tyrosine kinase families. The phase I/II HER2 vaccine trial continues to enroll patients and is investigating the combination of vinorelbine, trastuzumab and a multi-epitope dendritic cell vaccine in the treatment of women with high HER2-expressing metastatic breast cancer. Immune response to HER2 has been detected and some trend for survival advantage is beginning to be shown.
In the second project, Dr. Earp's team is studying the EGF receptor family. The experiments over the last six months have investigated the signaling "downstream" from HER4 by studying WWOX, a tumor suppressor that binds to HER4. Their project has shown that HER4 can send both tumor promoting and tumor suppressive signals in breast cells depending upon which HER4 gene variant (isoform) is active. Studies of these HER4 isoforms have led to new studies on the tumor suppressor WWOX which binds to HER4. Additional techniques are being used to study the large scale changes in the protein kinome in breast cancer. Dr. Earp's team is also looking at a systems approach to measure the overall kinome response to ligands and growth factors and single kinase inhibitors using breast cancer pre-clinical models.
Lastly, Dr. Earp and colleages have an exciting breast cancer immune response project studying the role of a tyrosine kinase called Mer, which is identified by this lab. Their initial data (submitted for publication) demonstrates that Mer signaling creates, in part, the immunosuppressive phenotype produced by tumor-associated macrophages. Elimination of Mer signaling appears to help the immune system fight the mammary tumor in pre-clinical models.
Shelton Earp is a 1970 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.
His own 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 120 biomedical-research papers and has recently received a new R01 grant, in addition to serving 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 was recently elected to the board and as President of the American Association of Cancer Institutes. He is a recipient of The Breast Cancer Research Foundation funding for work to develop breast cancer vaccines, to understand the genetic predisposition to breast cancer, and to investigate breast cancer tumor suppressor function.