Grant: Project Grant

Many anti-cancer drugs cause side effects that damage the heart. Doxorubicin is one of the most commonly used anti-cancer drugs and is used to treat breast cancer, lymphoma, and many childhood cancers. However, up to 26% of patients who receive this drug experience cardiotoxicity, which can lead to heart failure, heart transplantation, and death. Currently, we lack the ability to predict which specific patients are at risk of this adverse drug reaction, and we have no effective methods to prevent it. The goal of this study is to investigate the function of specific genes that have been associated with doxorubicin-induced cardiotoxicity. By understanding if these genes directly impact the response to doxorubicin, and what biological mechanisms are involved, we could potentially use these genes as genetic tests to predict which patients are most likely to develop cardiotoxicity from this drug. We will study the role of these genes in heart cells generated from human stem cells. My lab has recently described a new way of studying doxorubicin-induced cardiotoxicity using such stem cell - derived heart cells. We will introduce the specific gene variants of interest using a state-of-the-art gene editing technology called CRISPR. We will compare heart cells with or without these gene variants to determine how they respond to doxorubicin. We will also isolate stem cells from the blood of patients that have suffered from doxorubicin-induced cardiotoxicity, turn these stem cells into heart cells, and study how they respond to the drug, in the presence or absence of the specific gene variants. If we can identify the patients at highest risk of drug-induced heart damage, we could take steps to prevent or mitigate this devastating adverse drug reaction. Ultimately these efforts will result in safer and more effective drugs and will allow Canadians to stay healthier and experience fewer side effects.