PHILADELPHIA - Researchers from the University of Pennsylvania School of Medicine and colleagues at Merck Serono Research in Germany have found that two drugs bind to receptor sites on some tumors in different places at the same time, suggesting the possibility of a new combination therapy for certain types of cancer.
An increasing number of therapies targeting tumors that have proteins called epidermal growth factor receptors (EGFR) sitting on their surface are already being used in the clinic or are in late stages of development. For example, Herceptin is an established treatment for certain types of breast cancer and Erbitux and Vectibix are in use for other types of cancer. An additional drug called matuzumab is in phase II clinical trials.
Three years ago, Kate Ferguson, PhD, Assistant Professor of Physiology, and colleagues determined the precise molecular details of how Erbitux, a colorectal and head and neck cancer drug, binds to its target on cancer cells. EGFR drugs halt cell proliferation by blocking EGFR’s molecular doorway, keeping hormones from binding and signaling tumor growth. X-ray crystallography provided a snapshot of the interaction between Erbitux and the extracellular component of the cancer cell’s receptors.
As is characteristic of many epithelial cancers - such as cancers of the colon, head and neck, breast, ovary, lung, and pancreas - the surface of cancer cells possess abnormally high levels of EGFR. In a cancer cell, an extracellular hormone binds to the outer piece of EGFR, and causes the inside part to kick off a series of reactions that signal the cancerous cell to replicate and divide.
In the present study, published in Cancer Cell, Ferguson and Merck colleagues found – again using X-ray crystallography -- that matuzumab binds in a different place from Erbitux. Their binding does not overlap, and they can bind to EGFR at the same time.
“These findings imply that a combination therapy using both types of EGFR drugs could be developed and tested,” says Ferguson. “This has important implications for the clinical use of matuzumab and for developing new therapies that target EGFR.”
The research was governed by a Supported Research Agreement between Merck KGaA and the Trustees of the University of Pennsylvania and is financially supported in part by Merck KGaA, and the National Cancer Institute. Kate Ferguson is the Dennis and Marsha Dammerman Scholar of the Damon Runyon Cancer Research Foundation.
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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.
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