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.
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.
|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 :|
|Gupte, Manisha; Umbarkar, Prachi; Lal, Hind (2017) Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line : Editorial to: ""Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes"" by N. Hammoudi et al. Cardiovasc Drugs Ther 31:229-232|
|Guo, Yuanjun; Gupte, Manisha; Umbarkar, Prachi et al. (2017) Entanglement of GSK-3?, ?-catenin and TGF-?1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol 110:109-120|
|Gupte, Manisha; Lal, Hind; Ahmad, Firdos et al. (2017) Chronic Neuregulin-1? Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes. J Card Fail 23:887-899|
|O'Farrell, Alice C; Evans, Rhys; Silvola, Johanna M U et al. (2017) A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. PLoS One 12:e0169964|
|Qin, Pu; Arabacilar, Pelin; Bernard, Roberta E et al. (2017) Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress. J Am Heart Assoc 6:|
|Zhou, Jibin; Ahmad, Firdos; Parikh, Shan et al. (2016) Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circ Res 118:1208-22|
|Jacob, Fabian; Yonis, Amina Y; Cuello, Friederike et al. (2016) Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. PLoS One 11:e0145937|
|Zhou, Jibin; Ahmad, Firdos; Lal, Hind et al. (2016) Response by Zhou et al to Letter Regarding Article, ""Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy"". Circ Res 119:e29-e30|
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