Rachel Schiff, PhD

2012-2013 BCRF Project:
(made possible by generous support from Macy's)
Co-Investigator: C. Kent Osborne, MD, Baylor College of Medicine, Houston

Effective targeted treatments against estrogen receptor positive (ER+) and HER2 positive (HER2+) breast cancers are currently available in the clinic. However, many tumors present with, or will later develop, resistance that results in tumor progression and eventual patient death. Drs. Osborne and Schiff have recently developed multiple models including the PTEN KD model, which are resistant to targeted therapies against these pathways. The goals of their research are to continue the characterization and molecular profiling of these models and to identify novel targets and optimal combination treatments that can be then tested in the clinic to improve response and patient outcome. In 2012-2013, Drs. Osborne and Schiff will further explore the role of signaling derived from the surrounding tissue and molecules (the microenvironment) of the tumor in endocrine resistance.

Mid-year Progress: Effective targeted treatments against estrogen receptor positive (ER+) and HER2+ breast cancers are currently available in the clinic, but intrinsic or acquired resistance is prevalent. The goals of Dr. Osborne and Schiff's studies are to construct and characterize new models of resistance that will allow 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. The PI3K pathway is a key mediator of growth factor receptor (GFR) signaling and is one of the most altered pathways in breast cancer. The researchers have previously reported that the more aggressive and endocrine resistant luminal B subtype of breast cancer is associated with increased PI3K activity. Their recent studies suggest that reduced levels of the tumor suppressor PTEN, a negative regulator of PI3K pathway, is an important way by which breast tumor cells deregulate and activate this aggressive pathway. Using a genetic system that integrates inducible PTEN loss and a live animal-imaging platform, the group led by Drs. Osborne and Schiff find that low PTEN activates multiple downstream kinase signaling as well as reduces endocrine sensitivity and renders therapy resistance to therapies. To overcome this resistance, they have evaluated the combinational effects of various inhibitors against key PI3K-downstream kinases and showed the therapeutic potency of combining fulvestrant, a selective estrogen receptor downregulator (SERD), and an AKT inhibitor (AKTi) in murine xengraft models with low tumoral PTEN levels. They have also optimized a PTEN IHC assay and are currently further investigating the association between tumor PTEN levels and response to endocrine therapy using clinical material. Analysis of gene and protein expression profiling of this and additional endocrine resistant models are underway to interrogate the relationship between ER and additional master transcriptional regulators and GFR/kinase signaling pathways.

Bio:
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.