Multiscale Systems to Elucidate Susceptibility and Cardioprotective Mechanisms in Cardio-oncology

PROJECT SUMMARY (OVERALL) The overarching goal of this Program Project Grant (PPG) is to elucidate mechanisms of cardiotoxicity and to develop a platform to test cardiotoxicity of new cancer therapeutics. Project 1 (Moslehi) will use a combination of mouse- and cell-based models to address the central question of whether cardiotoxicity associated with ibrutinib is on- or off-target. Project 2 (Wu) will establish novel pooled “cell villages” from patients to map genetic inter-individual difference in response to kinase inhibitors to elucidate genetic susceptibility to cardiotoxicity from kinase inhibitors. Project 3 (Mercola) aims to identify mechanisms that protect against cardiotoxicity of ibrutinib using a pipeline for discovery of protective targets based on reverting epigenomic consequences of exposure to a toxic drug. All three projects will be supported by an iPSC Processing Core (Core B) (Sallam) that will facilitate a unique repository of iPSC lines from patients with ibrutinib treatment. An Administrative Core (Wu) will support all three projects and the core to facilitate a fully integrated program project and enable high- impact research. The proposed PPG and assembled group collectively introduces synergies that will significantly impact the field of cardio-oncology and make translationally actionable inroads to decrease the burden of adverse effects of cancer therapeutics.