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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 improve treatments and outcomes for patients with HER2-positive breast cancer.
Impact: Dr. Pegram has developed a new therapeutic strategy to stop tumor growth in HER2-postive breast cancer patients. He is now focusing on a pathway that prevents an anti-tumor immune response and is blocked in HER2-positive breast cancer. His team is investigating new therapeutic combinations to restore immunity in HER2-positive breast cancer and improve treatment strategies.
What’s next: He and his team will characterize and target a pathway to restore immunity to fight 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, HER2-positive breast cancers are resistant to these drugs and many become resistant to them over time. Dr. Pegram is studying a pathway that blocks anti-tumor immune system activity. Restoring this immune response in combination with targeted therapies may lead to breakthroughs for those with advanced HER2-positive breast cancer.
Full Research Summary
Research area: Identifying mechanisms underlying immune response and investigating new therapeutic strategies aimed at restoring anti-tumor immunity.
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 is now studying other vulnerabilities in HER2-positive breast cancer and developing novel therapeutics to fight the disease.
Current investigation: Dr. Pegram’s team recently discovered that HER2 inhibits a signaling pathway called STING, an important component in activating the body’s anti-tumor response. Dr. Pegram believes that the STING pathway can be reestablished with STING-activating drugs in combination with anti-HER2 treatments, and that this will restore innate immunity and anti-tumor activity. Understanding the mechanism of this pathway will promote discovery of more effective immune therapies for treatment of HER2-positive breast cancer.
What he’s learned so far: Dr. Pegram and his team have shown that amplifying HER2 in a breast cancer cell model decreases STING expression compared to other breast cancer subtypes and that the STING pathway can be restored with STING-enhancing therapies plus trastuzumab.
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.