Target Validation, Cardiovascular, Cellular Signalling

Anti-cancer drug cardiotoxicity is a growing concern for oncologists and cardiologists as well as the pharmaceutical industry. It is now recognised that anti-cancer drugs from the tyrosine kinase inhibitor family exhibit detrimental effects on cardiovascular function. Most of the work to date has focused on  the effects of these drugs on the heart. It is highly likely that the toxic effects are also evident in the vasculature, however far less is known about how this manifests. The endothelium of the vasculature is the inner-most layer of the vessel and plays a pivotal role in sending and communicating signals across the vessel, allowing rapid responses to changes in environment. As such, any impairment in endothelial function results in vascular dysfunction with knock-on effects on the heart. 

Previous work by our group has explored the effects of two anti-cancer agents, sunitinib and imatinib, on various cardiac parameters both in vivo and in isolated primary cardiac cells in culture. We have verified that both agents induce detrimental effects on cardiac cells after both acute (hours) and chronic (days) treatments. Preliminary work using primary endothelial cells suggests that similar detrimental effects are observed and that these cells may be more sensitive to the anti-cancer drugs than the cardiac cells. The cellular mechanisms that underlie these effects remain unknown. Identification of intracellular targets and mechanisms of action will be crucial in the drive to improve cancer treatments.

The purpose of the current project will be to explore these effects further and specifically in the vasculature. In particular, this project will determine how anti-cancer drug mediated alterations in endothelial cell signalling might lead to pathophysiological changes at a cellular level. The project will examine effects on oxidative stress and mitochondrial function and will investigate whether intervention strategies targeting specific intracellular signalling pathways might prove to be beneficial is reducing or reversing the detrimental effects of these agents.

Aortic tissue isolation and organ bath work, primary endothelial cell isolation and culture, kinase assays, proliferation assays, cell imaging and immunofluorescence, immunoblotting, immunoprecipitation, mitochondrial functional assays, siRNA work. 

Kerkela R. et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine 12, 908-916

Barr L.A. et al (2014) Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. Clin.Transl.Sci. 5, 360-367

Mooney L. et al (2015) Effects of acute and chronic sunitinib treatment on cardiac function and CaMKII. Br.J.Pharmacol. 172, 4342-4354