Mitigation of human drug-induced proarrythmia and cardiotoxicity of oncology therapeutics

Cardiotoxicity is a major complication of many anticancer therapies, impacting the quality of life and overall survival of the patient, manifesting as both an acute toxicity (days/weeks) and frequently a chronic toxicity occurring months/years after conclusion of therapy. These cardiotoxicity concerns have an impact on treatment regimes, with patients potentially receiving suboptimal therapy, resulting in increased mortality. Molecular targeted chemotherapeutics are now commonplace within the clinic. Many of these compounds cause cardiotoxicity, shown by electrocardiographic changes and alteration of cardiomyocyte function. The observation of these changes within hours of drug exposure, and in a quiescent or slowly-proliferative cellular population, supports the existence of novel mechanism of cardiotoxicity independent of a direct antiproliferative effect. Therefore, further interrogation of the underlying mechanisms of toxicity of these drugs is required to improve our understanding of the clinical issue and mitigate against longer-term chronic cardiotoxicity.
Hypothesis: Molecular targeted anticancer agents cause cardiotoxicity via interruption of cardiomyocyte excitability and/or changes in the mechanistic basis of cardiomyocyte contractility.
Aims:
1. Characterisation and validation of the in vitro models for assessment of drug-induced effects upon contractility and viability. Within the project we will be develop vitro models of cardiac contractility using immortalised ventricular and atrial cardiomyocyte cell lines, and human induced pluripotent stem-cell derived cardiomyocytes (hiPSC), in combination with human fibroblasts and endothelial cells, which closely emulates the in vivo system. These models will be characterised for contractility against ‘standard’ pharmacological modulators of ion channel and non-ion channel targets. This should inform us of the strengths and limitations of each cell model, and will provide a strong base and comparative data for assessment of the chemotherapeutics within this project.
2. Identification of the effects of molecular targeted cancer chemotherapeutics upon cardiac viability and contractility. Drug-induced cardiotoxicity has many manifestations, including multifocal cardiomyocyte death, cardiac hypertrophy, perturbation of contractile function and induction of ventricular repolarisation and arrhythmias. Using the model systems we will assess specific anticancer therapeutics. We will characterise both time-dependent and dose-dependent effects on cardiomyocyte viability, hyperplasia, hypertrophy, and contractility. Throughout this phase of the project, in vitro results will be compared to clinical data where available. Differences in genetic expression profiles between treatment groups will be assessed to identify common/novel molecular pathways and permit maximum information from each experiment.
3. Mitigation of acute cardiotoxicity through co-administration of cardiovascular therapy. Perturbations in cardiac contractility are directly relatable to alterations in the ion channels controlling the cardiac action potential, clinically controlled via pharmacological interruption of the specific Na+, K+ or Ca2+ channel. We will investigate whether pre-treatment of cardiomyocytes with these agents, e.g. β-blockers (Propranolol) and Ca2+ channel blockers (verapamil), can reduce the acute-cardiotoxicity of the various kinase inhibitors. In addition to the elucidation of the mechanistic basis of the toxicity, the observations from this phase of the project would have direct applicability to the clinic.
Methods and relevance to clinical therapy: This project offers an exciting and challenging study in the cardiotoxicity area, which is internationally highly topical, clinically relevant, and impacts on clinical treatment and the wider toxicological landscape. It will focus on translational studies of drug-induced detrimental effects upon the heart and will address the critical issue of how we can predict and manage this potentially life-threatening process. Thus, in addition to understanding the mechanisms underpinning drug-induced cardiotoxicity, the information and methodologies used in this study have broad applicability for preclinical toxicological evaluation of other therapeutic options. Overall, this project provides important data to significantly improve our understanding of drug-induced cardiotoxicity, and development of robust screening tools to achieve these goals.