Evaluation of methodologies for in vitro prediction of human drug-induced proarrhythmia and cardiotoxicity of oncology therapeutics

Increased understanding of the molecular basis of many life-threatening diseases, such as cancer, has led to the development of advanced therapies as “targeted molecular therapeutics”. Although many of these ‘blockbuster’ drugs have proved very successful in the clinic and improved treatment success rates, it is now becoming apparent that many of these therapies are not as ‘targeted’ as predicted and are accompanied by safety issues and side effects. Consequently, there is a greater requirement by the pharmaceutical industry to better understand the prevalence and mechanism of these potentially life-threatening secondary effects, in order to market safer medicines.

Adverse effects upon the cardiac system are now known to be a major concern for many new targeted therapeutics. Drug-induced acute cardiotoxicity has many manifestations, including destruction of heart tissue, enlargement and functional restriction of the heart, perturbation of heart contraction and induction of an irregular heartbeat (arrhythmia), many of which can be fatal. A major underlying problem is that current methodologies to efficiently and robustly identify this liability in the laboratory are suboptimal, with many false-positives and false-negative inhibitory drugs being identified, and subsequent cardiac events not being identified until either late stage development or the clinic. Therefore the challenge is to develop improved approaches and preclinical screens to better predict and understand the mechanistic basis of drug-induced cardiotoxicity potential.

The objective of this PhD project is to use stem-cell derived cardiac cells and cell lines as tools for evaluating the physiological and pathological responses to targeted therapeutics, and determination of their underlying molecular mechanisms of toxicity. This will be achieved using state-of the-art impedance based cell screening technologies for in vitro assessment of cardiac contractility. One such assay technology, the xCELLigence realtime analyser (RTCA) system, has recently been installed within the medicines safety assessment facility of the School of Medicine, Pharmacy and Health. The technology allows real-time label-free assessment of rhythmic contraction of cardiomyocytes, and the effects of drugs thereon, allowing pharmaco- and toxicodynamic effects to be monitored over time. The overall goal of this project would be improved predictability of drug-induced cardiotoxicity, with significant impact upon current legislative methodologies and procedures, and the consequent implementation of a reductionist strategy for the use of in vivo animal models in the early drug screening process.