Department of Medicine, Breast Center
Baylor College of Medicine
Co-Investigator: C. Kent Osborne, MD, Baylor College of Medicine, Houston
Effective targeted treatments against the estrogen receptor-positive (ER+) and HER2+ breast cancers are currently available in the clinic, but tumor resistance is common. The goals of Drs. Osborne and Schiff’s studies are to continue to characterize new models of resistance that will allow for genomic, molecular, and therapeutic studies aiming to identify key molecules responsible for treatment resistance and to develop new treatment strategies that will improve response and patient outcome. In 2013-2014 Drs. Schiff and Osborne will continue to identify most effective drug combinations with a focus on novel inhibitors of kinase proteins activated by growth factor signaling and new agents, called SERDS, that can degrade the ER protein They will further investigate compensatory and feedback signaling induced in tumors in response to these drugs in order to understand how to prevent the acquisition a secondary resistance. The role of a few new potential genes in resistance to antiHER2 therapies will also continue to be explored.
Recent findings by Drs. Osborne and Schiff now suggest that both more common compensatory and adaptive mechanisms as well as the evolution of rare clones with unique (“personalized”) genomic and/or epigenomic features of resistance co-operate during the emergence of drug resistance. Specifically, they have identified a switch in ER activity that can stem from genetic aberrations and over-expression of ER co-regulators using models of endocrine resistance. Consequently, a specific set of cytokines known to regulate tumor survival and metastasis are induced. Inhibition of either the aberrant ER co-regulators or the cytokines can inhibit tumor cell growth and overcome resistance. Similarly, their studies also have identified unique genetic aberrations in resistance models to potent HER2-targeted therapies, including mutations in the HER2 receptor itself. The researchers will continue to characterize the adaptive and selected resistant mechanisms that operate in their resistant models, which represent genetic diversity of tumors in the clinic, and to identify new strategies and effective drug combinations to overcome them. Their recent studies also support the efficacy of a new oral compound that can degrade the ER protein (SERDs) and overcome tamoxifen resistance. They will continue to evaluate this drug and its mechanism of action with the goal to provide sufficient evidence for its clinical development.
Dr. Schiff is Associate Professor at the Baylor College of Medicine, Sue & Lester Smith Breast Center and the Departments of Medicine and Molecular and Cellular Biology. She is an internationally recognized expert in breast cancer translational research and in preclinical therapeutic models, especially concerning endocrine, HER2, and additional targeted therapies. Dr. Schiff has received her PhD in 1992 from Hebrew University Hadassah Medical School in Jerusalem and had completed her post-doctoral fellowship at University of Texas Health Science Center, San Antonio. She joined Baylor College of Medicine in 1999 as a faculty member of the Sue & Lester Smith Breast Center.
Dr. Schiff's research focuses on understanding key signaling pathways in breast cancer and on identifying therapeutic strategies to overcome them. Major interests include molecular aspects of estrogen receptor (ER) action in breast cancer, the crosstalk between the ER signaling network and growth factor receptor and cellular kinase pathways, the role of ER co-regulators in breast cancer development and progression, mechanisms of resistance to targeted therapies, and the identification of biomarker and signatures of hormonal and antiHER2 therapy resistance for therapeutic interventions. Dr. Schiff's research is partly supported by grants from the National Cancer Institute, BCRF, Susan G. Komen for the Cure, and the Department of Defense Breast Cancer Research Program.