Cancer-related pathways reveal potential treatment target for congenital heart disease

In two separate but related studies at University Health Network (UHN), Toronto, and Beth Israel Deaconess Medical Centre (BIDMC), Boston, the scientists proved that two drugs -- one already approved as an immunosuppressant, the other being tested as an anti- cancer agent- could prevent and reverse HCM in mouse models of congenital heart disease.

The research findings are published online February 21 ahead of the March issue of the Journal of Clinical Investigation. Both studies were co-led by UHN's Dr. Benjamin Neel, Director, Ontario Cancer Institute, which includes The Campbell Family Cancer Research Institute. Dr. Neel is also a Professor, Department of Medical Biophysics, University of Toronto, and holds a Canada Research Chair in Cell Signaling.

"By studying two of the most commonly mutated pathways in cancer, discerning the mechanism by which they cause congenital disease, and treating two of these disorders with different drugs, we have identified potential therapeutic targets for human disease," says Dr. Neel. "This is what personalized medicine is all about: understanding in detail how different mutations cause disease, and then targeting these mutations appropriately to tailor individualized treatment."

He adds: "These findings exemplify the importance of basic biological research and collaboration across areas of specialization. In this instance, collaboration showed how understanding cancer can lead to unexpected insights into congenital heart disease, and vice versa."

The scientists were investigating how a cluster of congenital diseases known as "RASopathies" -- defects caused by mutations in different genes in the so-called "RAS pathway" -- develop. They focused on two genetic disorders: Noonan Syndrome, which occurs in 1 in 1,000-2,500 live births and causes short stature, facial, blood and cardiovascular abnormalities; and the much less common LEOPARD Syndrome, which features short stature, as well as skin, facial, skeletal and cardiovascular abnormalities. HCM is prevalent in both syndromes.

The UHN study team, co-led by Dr. Toshiyuki Araki, Assistant Scientist, Campbell Family Institute and Dr. Peter Backx, Senior Scientist, Toronto General Research Institute and the Peter Munk Cardiac Centre, and Professor of Medicine, Division of Cardiology and Department of Physiology, U of T, investigated Noonan Syndrome. The Boston team, led by Dr. Maria Kontaridis, Assistant Professor of Medicine Harvard Medical School and Division of Cardiology, BIDMC, investigated LEOPARD Syndrome.

The scientists introduced the genetic mutations that cause these syndromes into special strains of mice, and were able to reproduce the features of the human disorders. The Toronto group found that "excessive activity of an enzyme called ERK, a downstream target of the RAS pathway, caused HCM in Noonan Syndrome, and successfully used a drug that lowers the activity of this enzyme to decrease pathway activity and normalize all of the features of Noonan Syndrome," says Dr. Neel. The Boston group found that LEOPARD Syndrome results from excessive activity of a different enzyme downstream of RAS, called mTOR. Using the mTOR inhibitor Rapamycin, which is already approved as an immunosuppressant, they were able to reverse HCM in their mouse model of LEOPARD Syndrome.

"These research findings are important steps towards understanding the pathogenesis of these congenital syndromes, and point the way toward clinical trials of these agents in severely affected patients," says Dr. Neel.

The research was financially supported by grants and fellowships from the National Institutes of Health, the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, the Frederick Banting and Charles Best Canada Graduate Scholarship, the Ontario Graduate Scholarship in Science and Technology, the Ontario Ministry of Health and Long Term Care, the Sao Paulo Research Foundation, the Milton Fund, the Beth Israel Deaconess Medical Centre Division of Cardiology, and The Princess Margaret Hospital Foundation.