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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
Goal: To prevent drug resistance and improve outcomes for patients with HER2-positive breast cancer.
Impact: Dr. Pegram has developed a new system for studying immune tolerance to HER2 antibody therapy, which will allow him to both identify the mechanisms underlying immune tolerance and investigate new therapeutic strategies to fight it.
What’s next: He and his team will study a highly innovative treatment approach that harnesses the body’s own antigen delivery system to target HER2-positive tumors.
HER2-positive breast cancer has become more treatable thanks to the development of targeted therapies such as Herceptin® (trastuzumab), which are extending the lives of many women with this type of the disease. However, others are resistant to these drugs or become resistant to them over time. Dr. Pegram is studying the role a patient’s immune system plays in the effectiveness of Herceptin®, which may lead to breakthroughs for those with advanced HER2-positive breast cancer that has stopped responding to current therapies.
Full Research Summary
Research area: Identifying mechanisms underlying immune tolerance and investigating new therapeutic strategies aimed at immune tolerance that will lead to new breakthrough treatments for HER2-positive breast cancer.
Impact: The discovery of Herceptin® (trastuzumab) has dramatically improved outcomes for many patients with HER2-positive breast cancer, which is more aggressive than other types of the disease. Despite this advance, up to 25 percent of women who initially respond to Herceptin® will experience a breast cancer recurrence within 10 years. Dr. Pegram, who played a major role in developing Herceptin®, is now studying how resistance to the drug develops in order to identify ways to overcome it.
Current investigation: Dr. Pegram’s team has been studying a highly innovative treatment approach that harnesses exosomes – small circulating vesicles primarily involved in cell-cell communication that have recently emerged as a promising drug delivery system. Dr. Pegram’s team is utilizing specialized exosomes to deliver a toxic payload to HER2-positive breast cancer cells. The exosome contains an inactive form of a drug – a prodrug – and genetic instructions to the cell on how to convert the prodrug to its active form. Because the exosome is designed to target only cells that have HER2 and because the drug is harmless until it gets in the cell, the therapy should not affect healthy cells.
What he’s learned so far: Dr. Pegram’s current study evolved from other ongoing work, in which he and his collaborators devised a system to deliver an inactive form of a toxic drug along with specialized RNA to provide gene editing instructions to make an enzyme to activate the drug once it is inside the cells – in this case cells that have HER2 protein on the cell surface.
What’s next: The team will use exosomes to deliver an enzyme to convert a non-toxic prodrug (tretazicar) into a tumor-killing drug that could be used to treat HER2-positive tumors.
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.