Cardiotoxicity of Tyrosine Kinase Inhibitors in Renal Cell Carcinoma
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Date
2017-03-29
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Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. The first line of treatment are tyrosine kinase inhibitors (TKIs), which inhibit vascular endothelial growth factors (VEGFRs), leading to inhibition of angiogenesis and delayed tumor growth. A commonly prescribed TKI known as Pazopanib inhibits VEGFRs 1-3 and platelet-derived growth factor receptors1. This drug leads to serious cardiac side effects in 50% of patients, including hypertension, heart failure (HF), and myocardial ischemia2-4. We believe that certain human populations are more susceptible to the cardiac side effects of Pazopanib and our goal is to gain a greater understanding of the mechanisms of these off-target effects as well as develop diagnostic tools to identify patients who would be more susceptible to this drug. We are currently using the murine mouse model to study the effects of Pazopanib in-vivo. Our data suggests that 8 week old mice treated with Pazopanib for 42 days have significantly increased blood pressure compared to control mice. Furthermore, our electrophysiological studies on isolated cardiomyocytes have revealed delayed after-depolarizations and prolonged action potentials, which are precursors to ventricular arrhythmias. These findings resemble the early side effects seen in humans and warrant further investigation. To observe TKI-induced HF we plan to repeat this experiment using two susceptible mouse populations. The first population will undergo transverse aortic constriction, a well-established procedure that has been shown to accelerate hypertension and HF. The second population will be null for a cardiac isoform of a cytoskeletal protein, beta-II spectrin in order to study the effects of this therapy in a structural heart disease model. These studies will allow us to unravel the mechanisms of Pazopanib cardiotoxicity and potentially lead to the development of novel diagnostic tools.
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Biological Sciences (The Ohio State University Denman Undergraduate Research Forum)
Keywords
Tyrosine Kinase Inhibitors, Cardiology, Renal Cell Carcinoma, Cardio-Oncology