This Project is focused on two critical issues that many cancer patients have to face: 1) the cardiotoxicity resulting from the use of anti-cancer drugs that injure the heart and 2) the cardiac dysfunction that arises from cancer induced cardiac cachexia. Neither of these issues are sufficiently appreciated by physicians, and this leads to morbidity and, in some cases, mortality. In this Project we propose to address these deficiencies.
In Aim 1 we propose to employ the zebrafish as a tool to identify anti-cancer drugs from the class of protein kinase inhibitors. Whereas rodent models have not been very effective in identifying problematic kinase inhibitors, our preliminary studies suggest the zebrafish may be a viable sentinel. We have, and will, test this hypothesis on each of the 12 drugs that are currently on the market, and on additional agents that will reach the market in the future. Furthermore, we will use these drugs as tools to identify the roles played by various protein kinases in the heart- an area about which we know very little. This should allow us to predict problematic agents before they are in widespread use. The second issue will address is cancer-induced cardiac cachexia, its consequences on the heart, and the signaling pathways that regulate it. Cachexia and its sequellae are estimated to be the cause of death in approximately 30% of cancer patients. Most importantly, we have outlined strategies, based on our findings in rodent models that limit or prevent cancer-induced cardiac cachexia. Remarkably, these strategies rely on agents that have been used in heart failure patients for years. Since these drugs are already FDA-approved for use in heart failure patients, we are proposing to go to clinical trial with these agents if our findings in additional rodent models concur with our completed studies. In summary, we believe that our studies could lead to novel diagnostic and therapeutic approaches to better the lives of cancer victims.

Public Health Relevance

We first brought to light the fact that cancer drugs that target protein kinases can have serious side-effects. There are literally hundreds of these drugs in development, and if we do not develop viable strategies to identify which of these agents will cause cardiotoxicity, we will have a significant problem on our hands. Similarly, the scourge of cancer cachexia, and its consequences on the heart, also needs to be aggressively addressed, and we plan to do so.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
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Vanderbilt University Medical Center
United States
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Gupte, Manisha; Tumuluru, Samvruta; Sui, Jennifer Y et al. (2018) Cardiomyocyte-specific deletion of GSK-3? leads to cardiac dysfunction in a diet induced obesity model. Int J Cardiol 259:145-152
Singh, Anand Prakash; Umbarkar, Prachi; Guo, Yuanjun et al. (2018) Inhibition of GSK-3 to induce cardiomyocyte proliferation-a recipe for in situ cardiac regeneration. Cardiovasc Res :
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