Stanford University School of Medicine
Director, Clinical and Translational Research Unit
Associate Dean, Clinical Research Quality
Susy Yuan-Huey Hung Endowed Professor of Medical Oncology and
Associate Director for Clinical Research,
Stanford Cancer Institute
Improving treatments and outcomes for patients with triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is arguably the most aggressive clinical subtype and due to the lack of targeted therapies, represents a disproportionate share of breast cancer mortality—this makes developing strategies to treat TNBC an urgent research priority. Therefore, Dr. Pegram and his colleagues are focused on designing a novel treatment for these patients, with a particular interest in a tumor promoting pathway driven by leukemia inhibitory factor (LIF). Elevated levels of LIF are observed in invasive breast cancers compared with normal breast tissues and significantly associated with a poorer relapse-free survival in breast cancer patients, indicating that LIF functions as a growth factor to promote tumor growth and invasion. Dr. Pegram is developing novel constructs to prevent LIF from binding to its receptor (LIFR). Through a series of experiments, he hopes to demonstrate that interference with LIF/LIFR binding as a novel strategy to treat TNBC.
His team engineered a variant of the LIFR protein (eLIFR) that traps and prevents LIF from binding to its receptors. It works by acting as a receptor decoy. It looks like a normal LIF receptor but its connection with LIF protein is 50-times stronger and it competes directly with normal LIF/LIFR binding on tumor cells. These receptor decoys have emerged as potential effective treatment alternatives to therapeutic antibodies. These findings indicate that the LIFR decoy may be a potentially effective treatment for breast cancer by preventing LIF/LIFR-induced tumor growth and invasion, particularly in TNBC.
Moving forward, the team will conduct investigations to measure LIF/LIFR protein expression in primary breast tumor specimens with a particular focus on clinico-pathologic and demographic variables in TNBC clinical specimens. Preclinical laboratory studies will assess the anti-tumor effects of the decoy in TNBC models. Through successful completion of their experiments, Dr. Pegram anticipates the results will support an investigational new drug application and a future phase I clinical trial of eLIFR.
Mark D. Pegram, MD is a renowned clinician and scholar in breast cancer research and a leader in translational medicine. Dr. Pegram played a major role in developing the drug Herceptin as a treatment for HER2-positive breast cancer, which constitutes about 20 percent of all cases. His laboratory experiments demonstrated that combining Herceptin with chemotherapy effectively killed cancer cells that overproduced the growth factor HER2. Dr. Pegram and others then conducted clinical trials showing that Herceptin improved survival rates and even cured some breast cancer patients. This remains one of the premier examples of bench-to-bedside translational research. Dr. Pegram’s current research efforts include a continued focus on the cancer-associated gene that encodes HER2 and developing new ways to target cancer cells expressing this protein. He is also pursuing strategies to target estrogen receptors, implicated in some 70 percent of all breast cancer cases.
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