A safety screening platform for individualized cardiotoxicity assessment.

Area of Science:

• Stem cell biology
• Cardiovascular toxicology
• Pharmacology

Background:

• Drug-induced cardiotoxicity is a significant clinical challenge, leading to treatment withdrawal and limiting cancer therapy efficacy.
• Current animal models lack predictability for human cardiotoxicity, and identifying at-risk patients remains difficult.
• Human pluripotent stem cell (hPSC)-derived cardiomyocytes offer a scalable and potentially personalized approach to assess drug safety.

Purpose of the Study:

• To develop and validate a platform using hPSC-cardiomyocytes for predicting molecular and functional cardiotoxicity.
• To differentiate cardiotoxic mechanisms of anthracyclines (Doxorubicin, Aclarubicin, Amrubicin).
• To evaluate the potential for individualized cardiotoxicity assessment in cancer patients.

Main Methods:

• Utilized a platform based on hPSC-derived cardiomyocytes to assess cardiotoxicity.
• Analyzed molecular (transcriptome, transcription factors) and functional (contractile force, mitochondrial integrity) endpoints.
• Investigated the effects of Doxorubicin, Aclarubicin, and Amrubicin, including recovery and repeated dosing.

Main Results:

• The platform successfully discriminated between the cardiotoxic profiles of Doxorubicin, Aclarubicin, and Amrubicin.
• Doxorubicin and Aclarubicin significantly impacted transcriptome, mitochondrial function, contractility, and transcription factor availability, unlike Amrubicin.
• Cardiomyocytes demonstrated full recovery within 2-3 weeks, mirroring clinical intermittent dosing, and the system allowed evaluation of cumulative dose effects.

Conclusions:

• hPSC-cardiomyocyte platform accurately predicts anthracycline cardiotoxicity mechanisms and severity.
• The system enables the study of cardiomyocyte recovery and cumulative toxicity, paving the way for personalized risk assessment.
• This approach has the potential to improve cancer patient safety by predicting and mitigating heart failure risk.