Postgraduate research opportunities Anti-cancer cardiotoxicity and metabolic mechanisms in healthy and diseased hearts

Drug-induced cardiotoxicity is a major concern in the field of cancer. A variety of anti-cancer agents result in damage to the heart and this is of major concern, particularly for patients who are already cardiovascularly compromised. These patients may be even more susceptible to the toxicity of anti-cancer therapy. Improved understanding of how anti-cancer drugs exert their effects on cells of the heart in healthy and cardio-compromised conditions is required in order to design better approaches for treatments that circumvent off-target toxic effects of these drugs on the heart. In particular, there is a need to understand the mechanisms that are disrupted by these drugs in both contractile and non-contractile cells of the heart. Key mechanisms that could be adversely affected include (i) calcium signalling and contractility in cardiomyocytes (ii) proliferation, extracellular matrix deposition and phenotype switch in cardiac fibroblasts and (iii) mitochondrial function and metabolism across both cell types. 

Since the effects of anti-cancer cardiotoxicity are often only evident after significant changes in cardiac viability and functional output, improved diagnostics are urgently needed to enable early detection of potentially toxic effects before functional deterioration occurs. Metabolomic research provides a valuable approach to identify potential markers of cardiac damage that may be detectable prior to obvious clinical manifestations in the patient. This technique has already been used to study metabolic changes occurring in the transition to heart failure. Anti-cancer therapy can result in complications such as hypertrophic remodelling, arrhythmogenesis and fibrosis, all of which can contribute to heart failure. Metabolomic research could make a valuable contribution to our knowledge of alterations in metabolic profiles that may contribute to predisposition to anti-cancer drug-induced cardiotoxicity.

Unanswered questions/aims of the project

• Does anti-cancer therapy result in dysfunction at the level of both contractile and non-contractile cells of the heart?
• Are cardio-compromised hearts more susceptible to the effects of these drugs?
• Are there specific metabolic profiles associated with anti-cancer drug treated cardiac cells that would allow identification of early onset biomarkers of cardiotoxicity? 

Techniques used

In vivo drug administration and echocardiography, immunohistochemistry, tissue and cell imaging, calcium imaging and signalling-based assays, primary cell isolation, protein assays, quantitative immunoblotting, proliferation-based assays, mass spectrometry

Project suitable for

• Fully-funded students
• Self-funded students
• Joint supervision with International institutions or places of work
• PhD plus