Grant: Project Grant

Chemotherapy-induced cardiotoxicity (CIC) is a very common complication of many anti-cancer agents and although cancer therapies maybe suppressing tumor growth, these patients begin to develop heart failure. Therefore, a better understanding of the signalling pathways involved in CIC are desperately needed, as there are currently no therapies that prevent the onset of this condition and most patients eventually die of either cancer or heart failure. One of the challenges in designing appropriate therapies to prevent CIC is selectively protecting the heart without preventing the benefits of cancer therapies against tumors. An intriguing difference between the heart and the tumor environments are the levels of oxygen (the molecule we breathe and required for life). The heart is present in an area of high oxygen levels, while the tumor can survive in areas of low oxygen. Therefore, screening for oxygen-sensitive proteins that may be induced by CIC agents in the heart may provide targetable therapies that are selective to the heart, without interfering with the anti-cancer effects of promising cancer therapies in the tumor. We have identified a candidate oxygen-sensitive protein called pyruvate kinase M2 (PKM2) that is induced in the heart by CIC agents. Intriguingly, drugs that activate PKM2 has previously been shown to suppress tumor growth, however, PKM2 function in the heart remains elusive. We show that activating PKM2 in the heart, where oxygen levels are high protects against CIC, but maintains and in some cases even enhances cancer therapy-mediated regression of the tumor, where oxygen levels are low. The therapeutic implications of this project may provide drug discovery platforms that could directly prevent CIC, which are desperately needed, but may also be applicable to other metabolic pathologies, including other forms of heart failure, cancer and diabetes.