Grant: Project Grant

Cardiovascular diseases and cancer are the two leading causes of mortality and morbidity worldwide. PI3Kalpha(a) is an interesting molecule as it is involved in both, heart physiology and cancer development, but it plays opposing roles in these two scenarios. In the heart, PI3Ka is required for healthy function, whereas in cancer, its inhibition has become the most effective treatment in anti-cancer therapies. As such, several drugs have been developed that directly/indirectly target PI3Ka. As a result, cancer patients who receive these drugs show promising improvements in tumor growth regression and recovery from cancer, but a significant fraction of them end up with heart failure. While the adverse effects of the anti-cancer drugs on the heart and the vasculature are now well established, the molecular mechanism underlying these unfortunate side-effects have not been yet determined. Our research to date has identified PI3Ka, an enzyme that mediates various cellular responses (growth, death, proliferation) as the key player. We have generated genetic mouse models that lack PI3Ka in specific cells (cardiomyocytes in heart; endothelial cells in vessels). We have also obtained the pharmacological inhibitor of PI3Ka, BYL719, currently in clinical trial for anti-cancer therapies. We will use our genetic models, and the pharmacological inhibitor of PI3Ka, in combination with models of heart disease, and other conventional anti-cancer drugs to reveal the central role of PI3Ka in the cardiovascular toxicities associated with anti-cancer treatments. We will take a comprehensive approach which will include animal disease models, functional assessment of heart and arteries, electrical activity of the heart, and detailed molecular/cellular analyses. We will also use the cancer patient registry in Alberta to determine the connection between the type of anti-cancer treatment/drugs that patients receive and the severity of cardiac and vascular complication