The development of kinase inhibitors (KIs) has revolutionized the treatment of a broad spectrum of cancer types. However drug-related adverse effects often counter the benefits of anti-cancer drugs. With the widespread use of KIs, it has become apparent that a subset of patients develops cardiac dysfunction and heart failure. Currently our knowledge of the underlying pathophysiology and risk factors is limited. Experiments focusing on understanding the molecular and genetic mechanisms underlying cardiotoxicity will be critical to improve and guide further drug development. The recent development of human induced pluripotent stem cells (hiPSCs) and the ability to differentiate hiPSCs into CMs (hiPSC-CMs) offer unprecedented opportunities for disease modeling and cardiotoxicity testing. Human iPSC-CMs exhibit properties highly similar to their primary counterparts, thus providing a relevant `patient in a dish' model. The overarching goal of this proposal is to identify and understand the molecular and genetic mechanisms underlying KI-induced cardiotoxicity by using hiPSC-CMs. The proposal builds on extensive infrastructure funded through various NHLBI grants. We have generated 250 hiPSCs lines and differentiated these lines into CMs from participants in the NHLBI HyperGEN cohort. We propose to use these hiPSC-CMs to identify underlying pathways and genetic markers, which contribute to the variability in the response to KIs. Using expression analysis, we will describe the distinct molecular responses associated with exposing hiPSC- CMs to KIs. We will perform standard phenotypic analyses, expression analysis and functional assays for cardiotoxicity. Subsequently we will perform pathway expression analysis to identify novel functional networks associated with KI cardiotoxicity. In addition, we will be utilizing previously obtained GWAS and whole exome sequencing data to perform expression quantitative trait locus analysis to determine variants associated with KI-induced cardiotoxicity. Our proposal applies a precision and systems medicine approach to the study of cardiotoxicity. Furthermore the proposed approach can provide important insights for the future development of novel KIs with a reduced cardiotoxic risk profile.
Cardiotoxic effects contribute signficiantly to morbidity and mortality in a subset of cancer patients treated with kinase inhibitors. We propose to study the mechanisms and identify genetic markers using human induced pluripotent stem cell drived cardiomyocytes. Improving our understanding of the underlying mechanisms can improve cardiotoxicity testing, identify individuals at increased risk and guide the development of novel drugs with a reducted risk profile.