Targeted Approaches for Prevention and Treatment of Anthracycline-Induced Cardiotoxicity

• Paul BURRIDGE, Northwestern University Feinberg School of Medicine, Chicago (USA)
• Brian DRUKER, Oregon Health & Science University, Portland (USA)
• Rodolphe FISHMEISTER, INSERM, Châtenay-Malabry (France)
• Denise HILFIKER-KLEINER, Philipps-Universitat Marburg (Germany)
• Alexander LYON, Imperial College, London (UK)

The global cancer epidemic is growing with 14+ million new cases per year. Due to advances in detection and treatment, 50% of cancer patients will live 10 or more years with 18 million survivors in USA with a similar estimated survivor population in Europe. Part of this success is due to the effective use of anthracycline (AC) chemotherapy, but at the potential expense of damage to the patient’s heart. Despite such side effects, AC chemotherapy is effective at treating various cancers and remains widely used. Among the many cancer patients receiving AC, children with leukemia and adults with breast cancer are still treated and cured with these compounds, but around 10% of survivors are doomed to develop anthracycline-induced cardiotoxicity (AIC) and heart failure. This has recently raised interest in the emerging field of cardio-oncology but prevention, prediction and treatment of AIC are all still unmet medical needs. The mechanisms of AIC appear mainly based on toxicity to the mitochondria in the heart muscle cells. However, the specific details of the biology leading to dysfunction of mitochondria in the heart muscle after AC chemotherapy are still largely unknown. In this Leducq Network, we will address this fundamental gap of knowledge by studying and characterizing the molecular pathways underlying AIC, and identifying new predictive, diagnostic, and treatment strategies for AIC. We will comprehensively interrogate pathways underlying the mechanism of AIC, with particular emphasis on mitochondrial dysfunction and key metabolic alterations. For these studies, we will use mouse models of AIC, stem cells and heart muscle samples from patients who developed AIC and compare them to those from patients receiving AC who did not develop AIC. By better understanding mechanisms and genetic predisposition, we aim at discovering blood-based biomarkers suitable for early prediction, as well as discovering innovative cardio-protective strategies to provide a safe and effective therapy for cancer.