Cardiotoxicity is a major limiting factor preventing dose-effective cancer treatment with many commonly-used and novel chemotherapeutic anti-cancer agents. If not diagnosed and managed effectively, cardiotoxicity can result in significant long term morbidity and mortality. Current diagnosis relies on deterioration of cardiac function which implies a high degree of cardiac damage, and offending agents are stopped or significantly reduced. More effective diagnostic and screening tools would allow for a more personalized approach to therapy including closer monitoring, prophylactic cardioprotective therapy, and dose/drug changes in at-risk patients. We hypothesize that myocardial cellular and quantitative tissue characterization with cardiac MRI (CMR) and positron emission tomography (PET) will provide sensitive imaging biomarkers for the detection of cardiotoxicity with changes that manifest prior to reduced cardiac function in patients treated with cardiotoxic agents. To explore this hypothesis, a pre-clinical mouse model of doxorubicin-induced cardiotoxicity will be used. In Aim #1, mice will be treated with short interval (8 days) high- and low-dose doxorubicin therapy to explore the impact of treatment on CMR biomarkers (including myocardial extracellular volume, myocardial edema, myocardial velocity, and strain) and PET biomarkers (specifically myocardial metabolism). Correlation of these biomarkers with cardiac histology as well as CMR assessed cardiac function will be assessed. In Aims #2 and #3, a chronic cardiotoxicity mouse model will be used that more closely simulates clinical treatment dose and timing. Changes in CMR and PET biomarkers will be assessed over 40 days and compared to histologic and functional changes. As a part of this experiment, cohorts co-treated with dexrazoxane and trastuzumab, which mitigate and exacerbate cardiotoxicity, respectively, will be used as a sensitivity analysis of our techniques. The ultimate goal of this project is to identify promising imaging approaches for cardiotoxicity diagnosis and screening to facilitate rapid translation to clinical trials.
|Effective start/end date||7/1/17 → 6/30/19|
- RSNA Research and Education Foundation (RR1602 (Award Letter 6/30/16))