C. Kent Osborne, MD

2012-2013 BCRF Project:
(made possible by generous support from Macy's)
Co-Investigator: Rachel Schiff, PhD, 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.

Dr. Osborne, Co-Director of the San Antonio Breast Cancer Symposium, opened the 2011 proceedings with a tribute to Evelyn H. Lauder. SABCS, the largest annual breast cancer meeting, was attended by nearly 8,000 participants from more than 90 countries.

Bio:
Dr. Osborne was born in St. Louis, Missouri and received his AB and his MD from the University of Missouri, both with honors. He completed his internship and residency at Johns Hopkins and followed this with three years as a Clinical Associate at the Medicine Branch of the National Cancer Institute. He was a faculty member at the University of Texas Health Science Center from 1977 until 1999 and became Chief of Medical Oncology in 1992. In 1999, Dr. Osborne moved to Baylor College of Medicine to direct a new Breast Center at Baylor College of Medicine and in 2004 he, in addition, was named Director of the Dan L. Duncan Cancer Center at Baylor.

Dr. Osborne's research interests have focused on the biology and treatment of breast cancer. He has published extensively on the role of growth factors in breast cancer pathogenesis, and he has also investigated the mechanisms of tamoxifen action and resistance in breast cancer. As previous Chairman of the Breast Cancer Committee for the Southwest Oncology Group, he directed numerous clinical trials investigating new treatment strategies in primary and metastatic breast cancer. Dr. Osborne currently directs the Baylor Breast Cancer Specialized Program of Research Excellence Grant. Dr. Osborne has authored more than 350 manuscripts dealing with the biology and treatment of breast cancer.