Cardiotoxicity from Cancer Therapy: A Translational Approach to Biomarker Development

Abstract

Cardiotoxicity From Cancer therapy: A Translational Approach to Biomarker Development. BackgroundHeart damage from cancer therapy is a significant problem for survivors. Some of the most effective treatments, such as anthracyclines, cause heart toxicity that can lead to significant morbidity and mortality. Cardiotoxicity also contributes to the loss of promising cancer drugs in early development and is notoriously difficult to predict. This translational project employs parallel pre-clinical and clinical studies to explore circulating biomarkers and cardiac magnetic resonance imaging (CMR) during development of anthracycline associated cardiotoxicity with the aim of finding biomarkers to aid clinical decision making and enable forward/back translation. Methods Pre-clinical work: A rat model of chronic anthracycline-induced cardiomyopathy was developed involving 8 weekly intravenous boluses of doxorubicin followed by a 4 week 'washout' period. A time course assessment of cardiac function using multiple MRI parameters was performed alongside a panel of circulating biomarkers measured prior to dosing. Clinical work: In parallel following ethical approval, 30 cancer patients receiving standard anthracycline chemotherapy were recruited. Serial CMR scans were performed using standard and new exploratory techniques before, during and after treatment and blood was taken to evaluate a similar panel of cardiotoxicity biomarkers using multiplex ELISA at corresponding time points. Results Pre-clinical results: Systolic and diastolic function declined progressively, culminating in left ventricular dysfunction (LVEF

Date of Award	1 Aug 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Alan Jackson (Supervisor), Caroline Dive (Supervisor), John Radford (Supervisor), Kim Linton (Supervisor) & Matthias Schmitt (Supervisor)