Circulating Micrornas And Cytokines As Prognostic Biomarkers For Doxorubicin-Induced Cardiac Injury And For Evaluating The Beneficial Effects Of Exercise.

Abstract Introduction: Cardiotoxicity and late cardiomyopathies compromise survival in >50% of childhood cancer survivors treated doxorubicin (Dox). Early intervention is important for initiating therapy to preserve heart function. There are no accepted biomarkers identifying which patients are at risk for developing cardiac problems and no interventions to inhibit the cardiac damage. Troponin has not proved useful for predicting Dox-induced cardiotoxicity and patient outcome. We developed a pediatric mouse cardiotoxicity model to define early biomarkers of Dox-induced cardiac injury, investigate the efficacy of an exercise intervention, and whether these biomarkers can be used as a non-invasive method to monitor exercise effectiveness. Hypothesis: Circulating micro-RNAs are increased during Dox but not Dox + exercise therapy which correlate with cardiac damage. These can be used to monitor intervention effectiveness. Methods: Mice were treat with Dox (2.5mg/kg 2x/wk for 2 wks), Dox + exercise (walking 45 min/day at 12 meter/min) or PBS. Cardiac function was evaluated by echocardiography 24 hrs after therapy. Blood was collect before and 6 and 24 hrs after therapy. Plasma cytokine levels, troponin and miRNAs (miRNA 1, 29b, 499) were quantified. We also obtained plasma samples from Dox-treated osteosarcoma patients. Results: Decreased ejection fraction and fractional shortening were seen in Dox but not Dox + exercise-treated mice. There was an increase in miR-1 and miR-499 and the pro-inflammatory cytokines IL-1α, IL-1β and IL-6, in Dox-treated but not Dox + exercise-treated mice compared with PBS controls. Troponin levels were not elevated until 24 hrs following therapy. Increased miRNAs and cytokines in the Dox-treated patient plasma samples 24 hrs after therapy mimicked the results observed in mice. Conclusion: These data indicate that miRNA499, miRNA1, IL-1α, IL-1β and IL-6 are early biomarkers of Dox-induced cardiac injury which predict cardiac functional changes and can be used to evaluate intervention efficacy during combined therapy. Following these biomarkers may also assist in identifying patients at risk for cardiac late effects and also enable intervention modification as needed. Citation Format: Prince Jeyabal, Eugenie S. Kleinerman. Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the beneficial effects of exercise [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2378.