Grant: Project Grant

Early cancer diagnosis and better treatment options have significantly increased the survival of cancer patients. However, the most common and severe adverse problem for these patients continues to be the development of heart failure as a direct consequence of their cancer therapy. This has resulted in the establishment of cardio-oncology programs, where the heart and tumor are investigated together, both clinically (patients are seen by a cardiologist and oncologist) and scientifically, to develop new therapies that can protect (or prevent) against chemotherapy-mediated heart failure, but also enhance chemotherapy-mediated tumor regression. We propose that several different chemotherapeutics, all of which are known to cause heart problems in cancer patients, can induce cell death (apoptosis) nonspecifically in the heart by activating one central signalling pathway, resulting in heart failure. We have evidence to suggest that these chemotherapeutics can activate a heart failure promoting protein that we identified as Znf281. Intriguingly, Znf281 can also promote tumor growth and metastasis (the spreading of the tumor to different distant organs and tissues), suggesting that inhibition of Znf281 could protect the heart, but at the same time decrease tumor growth and tumor spreading. Our team of investigators have developed the first specific and potent inhibitor of Znf281, and we have preliminary evidence that inhibition of Znf281 can prevent chemotherapy-mediated death of heart cells, but at the same time, enhance chemotherapy-mediated regression of the tumor, while also preventing its ability to spread to other tissues. This work provides a new and attractive therapy that is critically needed in the cardio-oncology field to preserve heart function, and limit tumor growth/progression.