Rapamycin shown to inhibit angiogenesis

New findings further support drug's role as cancer treatment

BOSTON – Scientists have long known that the blood vessels of tumors differ markedly from normal blood vessels. Now, a research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) has identified a signaling pathway which, when activated, transforms otherwise healthy blood vessels into the leaky, misshapen vasculature that characterizes cancerous tumors.

The findings, published in the August 2006 issue of Cancer Cell, additionally demonstrate that rapamycin, a compound used for immunosuppression in transplant patients and currently under investigation as a cancer treatment, can successfully block this signaling pathway--known as the Akt pathway-- in blood vessels. This discovery further enhances the drug's promise as a cancer therapy.

"There are three major hallmarks associated with tumor blood vessels," explains the study's senior author Laura Benjamin, PhD, an investigator in BIDMC's Department of Pathology and Associate Professor of Pathology at Harvard Medical School.

"First, unlike healthy blood vessels which are uniform in structure, a tumor's blood vessels balloon and narrow, forming a highly irregular shape. Second, the layer of smooth muscle that you would expect to find covering the blood vessels is inadequate, often resulting in only intermittent coverage. And last, a tumor's blood vessels are overly permeable or leaky."

The hypothesis that blood vessel formation in tumors is essential for the growth and spread of cancer was first proposed in the early 1970's, and in 1983, it was shown that tumors secrete a factor called VEGF (vascular endothelial growth factor) that induces the permeability associated with blood vessels in cancer.

In this new study, Benjamin and first author Thuy Phung, MD, PhD, of BIDMC's Department of Pathology, hypothesized that the Akt pathway was mediating many of the functions of VEGF in tumors, including the stimulation of blood vessels with abnormal structure and excessive leak. Using a mouse model that enabled them to activate the Akt pathway in healthy blood vessel cells – without the complicating influence of tumor cells – they observed that Akt-induced blood vessels demonstrated the very same abnormalities that are seen in tumor blood vessels. Moreover, adds Benjamin, "We discovered that simply removing the activated Akt was sufficient to reverse these vasculature changes."

The scientists then went on to treat the animals with rapamycin. As predicted, the agent blocked the Akt-induced blood vessel changes. In subsequent experiments, rapamycin reduced tumor growth and vascular leak in a mouse tumor model.

"This paper represents an impressive advance in our understanding of the mechanisms by which tumors generate the new blood vessels they need to survive and grow," says Harold Dvorak, MD, Director of the Vascular Biology Center at BIDMC and Mallinckrodt Professor of Pathology Emeritus at Harvard Medical School, in whose laboratory VEGF was first discovered 23 years ago. "This suggests an attractive new molecular target for cancer therapy."

Approved by the U.S. Food and Drug Administration (FDA) as an immunosuppressant agent, rapamycin is being tested in clinical trials as a cancer treatment.

"These new findings suggest that we should think about using rapamycin in regimens where anti-angiogenic therapy in cancer patients is desired," says Benjamin. "If human tumors respond in the same way that animal models have, rapamycin may normalize and diminish the tumor vasculature, and this is particularly exciting because these findings are clinically relevant today."

In addition to Benjamin and Phung, study coauthors include BIDMC investigators Donnette Dabydeen, BS, Godfred Eyiah-Mensah, BA, Marcela Riveros, MD, Carole Perruzzi, BA, Jingfang Sun, DVM, Rita Monahan-Earley, BA, Janice Nagy, PhD, Ann Dvorak, MD, and Harold F. Dvorak, MD; Keren Ziv, MS, and Michal Neeman, PhD, of the Weizmann Institute of Science in Israel; Ichiro Shiojima, MD, PhD, and Kenneth Walsh, PhD, of Boston University School of Medicine; Michelle Lin, PhD, and William Sessa PhD, of Yale University School of Medicine, New Haven, Connecticut; and David Briscoe, MD, of Children's Hospital, Boston.

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This study was funded, in part, by grants from the National Institutes of Health and the Israel Science Foundation.

Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks fourth in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.


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