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Mark Pegram, MD
Susy Yuan-Huey Hung Professor
Director, Breast Cancer Program
Co-Director, Translational Oncology Program,
Associate Director for Clinical Research
Stanford Cancer Institute
Stanford University, School of Medicine
- Seeking strategies to prevent drug resistance and improve outcomes for patients with HER2-positive breast cancer.
- A novel experimental model system is employed to identify pathways driving resistance to HER2-targeted drugs.
- These innovated studies will accelerate the discovery of new treatment for patients with advanced HER2-positive breast cancer.
Targeted therapies such as Herceptin® (trastuzumab) have changed HER2-positive breast cancer from a very bad disease to a treatable one. While these therapies are extending lives for many women, many others are resistant to anti-HER2 drugs or become resistant over time. Dr. Pegram is conducting studies to understand how this resistance occurs and has identified an immune factor that may play a key role. Ongoing studies will test this theory and may provide breakthroughs for patients with advanced HER2-positive breast cancer that has stopped responding to current therapies.
Full Research Summary
The discovery of Herceptin® (trastuzumab) dramatically improved outcomes for many patients with breast cancer that carries the HER2 protein. Long-term follow up clinical studies, however, have shown that up to one quarter of women who initially respond to Herceptin® will experience a breast cancer recurrence within 10 years.
Herceptin® works by binding to receptors on the surface of cancer cells, thereby blocking growth pathways inside the cells. Because Herceptin® is an antibody, it also elicits a tumor-killing process called antibody-dependent cell-mediated cytotoxicity (ADCC) through activation of specialized immune cells called natural killer cells. Hence, tumor cells face selection pressures from both the antibodies and the immune effector cells.
Dr. Pegram believes that tolerance to immune-mediated, tumor cell killing can lead to acquired Herceptin resistance in HER2-positive breast cancer. To study this phenomenon, his team developed an experimental model of Herceptin® resistance that mimics human disease.
This year, the team will continue to work to identify mechanisms underlying such tolerance, and to investigate whether reversal of such mechanisms will result in new breakthrough treatment(s) of HER2-positive breast cancer.
The long-term goals of this study are to characterize this resistance and to identify potentially new resistance pathways or markers that can be targeted with a drug that can be tested in clinical trials.
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.
BCRF Investigator Since