Nancy E. Davidson, MD
Director, University of Pittsburgh Cancer Institute and UPMC Cancer Centers
Associate Vice Chancellor for Cancer Research
Hillman Professor of Oncology
Professor of Medicine and Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine
Member, BCRF Scientific Advisory Board
2013-2014 BCRF Projects:
1) (The ANN INC. Award)
It is now recognized that breast cancer is actually a collection of molecularly distinct diseases and that these diseases result from an accumulation of genetic and epigenetic changes. (Epigenetics, or ‘above genetics,’ is the study of changes in gene expression caused by mechanisms other than changes in DNA.) Dr. Davidson's work focuses on the ability to identify and target epigenetic alterations because they are potentially reversible. Her team's special interest is the enzymes that regulate these epigenetic alterations that include DNA methylation and alterations to histone proteins that are associated with DNA. Their hypothesis is that targeting these enzymes might lead to reversal of cancer-promoting epigenetic changes, thereby providing a new approach to breast cancer treatment. Their recent work has provided novel insights into molecular mechanisms by which two families of enzymes, histone lysine specific-demethylases (especially LSD1) and histone deacetylases (HDACs), abnormally interact in human breast cancer cells. They have shown that triple negative breast cancer cells (TNBC or basal-like breast cancer cells that lack expression of estrogen and progesterone receptor and HER-2 proteins) are more sensitive to this approach than other subtypes of breast cancer cells. Their studies focus on the mechanisms underlying this sensitivity to learn how to apply novel epigenetic agents in the most favorable combination strategy. Information derived from these studies may validate if a subset of epigenetically silenced genes has potential to serve as a novel panel of biomarkers to predict or indicate the response to epigenetic therapy. These studies will provide critical information on whether the utility of a combination of LSD1 and HDAC inhibitors is more efficacious in reactivating aberrantly silenced genes and hindering breast tumor growth.
New targeted approaches are urgently needed to improve therapy for triple negative breast cancer (which lacks expression of estrogen and progesterone receptor and HER-2). Like other cancers, TNBC develops as a consequence of cumulative genetic and epigenetic changes. The epigenetic alterations include DNA methylation and histone tail modifications. The goal of this BCRF funded research is to understand how changes in interaction of chromatin-remodeling enzymes contribute to TNBC development and to test novel targeted combination approaches of epigenetic drugs to inhibit breast tumor growth. Dr. Davidson’s recent work suggests that TNBC has enhanced crosstalk between histone enzymes LSD1 and HDACs that promotes aberrant gene silencing and tumor cell growth, and that crosstalk between LSD1 and HDACs may represent a novel therapeutic target for TNBC. Moreover, her team’s recent studies have shown stable knockdown of LSD2, a homolog of LSD1, resulted in enhanced sensitivity to the DNMT inhibitor, decitabine, in MDA-MB-231 cells. Taken together, these results implicate an important role for FAD-dependent histone demethylases in regulation of chromatin remodeling and gene silencing in breast cancer and suggest that inhibition of FAD-dependent histone demethylases represents a novel approach to improve therapeutic efficacy of current epigenetic drugs in breast cancer.
2) On behalf of North American Breast Cancer Group (NABCG) and the Breast International Group (BIG)
The goal of the collaborative effort between the Breast Cancer International Group (BIG) and North American Breast Cancer Group (NABCG) is to reduce the burden of breast cancer through promotion of joint research efforts around the world. With BCRF support, investigators meet annually in the US or Europe to chart research directions and track progress. The April 2013 meeting in Washington DC focused on development of a proposal to investigate the molecular changes of metastatic breast cancer because it is this phase of the illness which is fatal and because other global efforts have focused largely on characterization of early breast cancer. The broad framework for a collaborative effort has been described, and specific proposals for the NABCG and BIG are being organized. Several working groups also continue to focus on important issues in endocrine therapy, male breast cancer, informatics, and use of Ki67. An important review on the needs of women with metastatic breast cancer has been published by NABCG/BIG investigators thanks to BCRF support.
The goal of the collaborative effort between The Breast Cancer International Group (BIG) and North American Breast Cancer Group (NABCG) is to reduce the burden of breast cancer through promotion of joint research effort around the world. Planning is underway for the 2014 meeting which will be held in Brussels, Belgium in May, 2014. Critical planning is ongoing in North America and in Europe for parallel efforts to perform sequencing analysis on metastatic breast cancer specimens as a way of trying to enable more tailored therapy for advanced breast cancer. These studies will be supported by the Founder’s Fund. Several working groups also continue to focus on important issues in endocrine therapy, male breast cancer, informatics, and use of Ki67. The Ki67 Working Group has published a key analysis of Ki67 measurement in the Journal of the National Cancer Institute and reported preliminary results of a study designed to improve researchers’ ability to measure this important marker of proliferation more reproducibly and reliably at labs around the world.
Dr. Nancy E. Davidson FACP is the Director University of Pittsburgh Cancer Institute and University of Pittsburgh Medical Center (UPMC) Cancer Center and Associate Vice Chancellor for Cancer Research at the University of Pittsburgh since February 2009. Dr. Davidson works as a physician-scientist in the biology and treatment of breast cancer. Her research has significantly advanced understanding of the molecular and cellular biology of breast cancer and pioneered new therapeutic approaches to the disease, particularly for patients who don’t respond well to current treatments. While her laboratory research has concentrated on epigenetic regulation of the estrogen receptor gene in breast cancer, the clinical and translational aspects of her work have led to national clinical trials to determine the efficacy of such treatments as chemoendocrine therapy for women with premenopausal breast cancer and antiangiogenesis therapy for those with advanced forms of the disease. She is a leader in the conduct of breast cancer clinical trials in the national setting, previously serving as chair of the Eastern Cooperative Oncology Group’s Breast Committee. She is the author of over 250 scholarly papers and has been continuously funded by the National Institutes of Health since 1989.
Dr. Davidson received her bachelor’s degree from Wellesley College and medical degree from Harvard Medical School. She completed internal medicine training at the University of Pennsylvania and Johns Hopkins and a medical oncology fellowship at the National Cancer Institute. She spent 23 years on the faculty at Johns Hopkins, serving as Professor of Oncology and Biochemistry and Molecular Biology and Director of the Breast Cancer Program at the Johns Hopkins Sidney Kimmel Cancer Center.
Dr. Davidson was president of the American Society of Clinical Oncology in 2007-2008 and has been an elected member of the Boards of Directors for the American Association for Cancer Research, American Society of Clinical Oncology, and Association of American Cancer Institutes. She serves on the external advisory boards for eight National Cancer Institute-designated cancer centers and is a member of the scientific advisory boards for the V Foundation for Cancer Research, Sidney Kimmel Foundation for Cancer Research, and The Breast Cancer Research Foundation. Among her many honors are the Brinker International Award for Breast Cancer Research, AACR-Women in Cancer Research Charlotte Friend Award, National Cancer Institute Rosalind E. Franklin Award, and American Society of Clinical Oncology Gianni Bonadonna Breast Cancer Award. She is an elected member of the Association of American Physicians and the Institute of Medicine.