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Penn preclinical study outlines cardiovascular side effects of breast cancer drug

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PHILADELPHIA – A receptor protein that is the target of the breast cancer drug trastuzumab (Herceptin) is needed for proper heart blood-vessel development, reported researchers from the Perelman School of Medicine at the University of Pennsylvania. They published their findings this month in Nature Communications. These discoveries have implications for better understanding the cardiovascular side effects of trastuzumab commonly used for cancer and provide an example of integration at the molecular level of pathways involved in tissue growth and blood-vessel patterning.

First author Haig Aghajanian, PhD, a postdoctoral fellow in the lab of senior author Jon Epstein, MD, a professor of Cell and Developmental Biology and executive vice dean and chief scientific officer for Penn Medicine, showed that ErbB2, a growth factor receptor, is unexpectedly expressed by vascular endothelial cells. Here it partners with neuropilin 1 to form a receptor for the vascular guidance molecule semaphorin 3d. Guidance molecules work by instructing the direction in which cells migrate, such as when new blood vessels are forming.

"ErbB2 is a well known target in cancer therapy, but not in vascular biology," Aghajanian said. "Our work identifies a new role for this important protein in blood vessel development and gives us a possible explanation for some of the cardiovascular side effects associated with anti-ErbB2 therapies."

They found that the loss of semaphorin 3d leads to improper connections of the coronary veins forming within the developing heart. They found a similar effect when ErbB2 was lost from developing heart-vessel-lining cells, providing a genetic link between these pathways.

The team was surprised when ErbB2 came up in their search for molecular partners for semaphorin 3d because semaphorin guidance molecules are not typically known to work through ErbB receptors.

"We questioned ErbB2's role at first," Epstein said. (ErbB2 had not previously been shown to even be in blood vessels.) "But now these findings give us a possible explanation for why there can be serious cardiovascular side effects, including heart failure, in patients receiving anti-ErbB2 therapies such as Herceptin."

Aghajanian and Epstein are using this knowledge to refine the hypothesis that targeting ErbB2 may also affect heart blood vessels leading to unwanted side effects. A better understanding of why the deleterious side effects are produced may lead to better ways to monitor and detect these unwanted effects before they cause symptoms.

"This work adds to an array of signals that affect how vessels grow and offers more targets to develop that promote or block the growth of blood vessels," Epstein said. These new targets could have implications for stopping the growth of certain tumors, abating ischemia, and alleviating diabetic retinitis.

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This study was funded by the National Institute of health (R01 HL118768), the Spain Fund, the Cotswold Foundation, and the WW Smith Endowed Chair.

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.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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