Grant: Operating Grant - PA: ICRH - New investigators (Bridge Funding)

Forty percent of Canadians will develop cancer in their lifetime. Doxorubicin is a one of the most commonly used and effective drugs to treat cancer, but it can cause heart damage in up to one-quarter of patients who receive it. We currently lack ways to predict or prevent this side-effect. Genetic studies have identified genetic variants that are associated with heart damage in patients that receive doxorubicin, suggesting that these variants may be useful to predict toxicity. However, whether these genetic variants directly influence response to this drug and via what mechanisms is unknown. The goal of this research is to understand how these specific DNA variants influence the response to doxorubicin. To investigate the function of these genetic variants, we will use a cutting-edge technique known as "genome-editing" that enables us to precisely alter the DNA sequence of human cells by introducing these genetic variants. We will perform this genome-editing in human stem cells, and use the stem cells to make heart cells that either contain or do not contain these variants. We will then treat the heart cells with doxorubicin to allow us to understand the functional impact of these genetic variants on the cardiac toxicity caused by this drug. These studies will determine whether these specific DNA variants are directly involved in the toxicity of doxorubicin and by what mechanisms. This information could lead to new strategies to predict which patients are most likely to suffer side-effects from this drug, and could also lead to the discovery of new protective agents to prevent this side-effect. Ultimately, this research will provide new tools to incorporate genetic information into clinical medicine to make our drugs safer and more effective.