Grant: Project Grant

Cancer therapies, including the anthracycline doxorubicin (Dox) is among the most effective and widely used antineoplastic agent for treating adult and pediatric cancers. However, despite its potent antitumor properties, a well-established but poorly understood feature of Dox therapy is its propensity for inducing heart failure in cancer survivors. Autophagy is an essential cellular quality control mechanism for the maintaining cardiovascular homeostasis and function. Loss of this cellular process results in heart failure. Growing evidence suggests that autophagy is regulated by the body's internal circadian clock that follows a 24hr light/dark cycle and that disruption of the body's clock such as seen in cancer patients profoundly influence cardiovascular disease outcomes. In this regard, growing experimental and clinical evidence suggests a link between circadian clock, autophagy and cardiotoxic effects of Dox. This proposal will address sex-specific differences and interplay between circadian disrupted autophagy and Dox -induced heart failure with the long term goal of developing new therapies that will mitigate the autophagy defect in cancer patients treated with Dox. Thereby reducing the cardiotoxic effects of Dox and improving quality of life.