Abstract 4368317: Identifying cardioprotective strategies against DOX-induced cardiotoxicity using mature, mitochondrial-rich and patient-derived hiPSC-cardiomyocytes

Abstract

Introduction: Doxorubicin (DOX) is widely used in cancer treatment but may cause mitochondrial damage and cardiotoxicity. Dexrazoxane is the only clinically approved intervention for DOX-induced cardiotoxicity (DCT); however, it may reduce DOX's anti-cancer effectiveness. The discovery of new drugs is hampered by the lack of appropriate human models and the challenge of balancing cardioprotection with cancer management. Aims: We aim to establish a clinically relevant model of DCT and identify novel treatment. Methods: We previously identified CD36 as a surface marker of CM maturation. Human pluripotent stem cell derived (hPSC)-cardiomyocytes (CMs) with high CD36 (CD36 hi CM) have more mitochondria. They also recapitulate the protective effects of dexrazoxane against DCT, unlike immature, conventional hiPSC-CM cultures. Here, we established a clinically relevant model of DCT using patient-derived hiPSC-CD36hi CMs. Using this model, we performed a targeted screen to identify compounds that can supress DCT. Selected candidates were further tested for their effects on a panel of cancer cells. Cardioprotective effects were then validated in mouse in vivo models. Results: Patient-derived CD36 hi hiPSC-CMs had more mitochondria and better mitochondrial function relative to CD36 lo CMs, and recapitulated the protective effects of dexrazoxane against DCT. Using this model, we identified drug candidates that can protect the mitochondria and increase CM viability. Further screening revealed a subset of candidates that do not affect or even suppress the viability of cancer cells. Echocardiography and histopathological examinations confirmed cardioprotection in vivo. Conclusion: Patient-derived CD36 hi CMs is critical for the identification of new treatment against DCT. Using this and an in vivo model, we identified candidates that suppress DCT without protecting or even suppress cancer.