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

Cross-disciplinary teams of scientists studying genetic pathways that are mutated in many forms of cancer, but which also cause certain forms of congenital heart disease – including hypertrophic cardiomyopathy (HCM), a thickening of the heart muscle that is the leading cause of sudden death in children and young adults –, have introduced these mutations into mice and successfully treated HCM in the lab.

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 today ahead of the March issue of the Journal of Clinical Investigation (manuscript # 44929). 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.