Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention

Abstract

Purpose of review: Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient's unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology.

Recent findings: Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology. When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals' treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.

Keywords: Cardio-oncology; Cardiovascular toxicity; Precision medicine; Prevention; Risk stratification; hiPSCs.

Fig. 1

Personalized and predictive health assessment using human-induced pluripotent stem cells (hiPSCs). 1, Patient diagnosis of cancer necessitating therapy with substantial potential for cardiovascular toxicity; 2, primary somatic cell types such as peripheral blood mononuclear cells (PBMCs) or fibroblasts taken from the patient to form their own cell line; 3, cultivating and differentiating hiPSCs to cardiomyocytes; 4, studying hiPSC-CM cellular response to chemotherapeutic agents; 5, individualized risk predictions based on cardiotoxicity risk profiles developed using patient’s own hiPSCs; 6, personalized therapy recommended for the patient; 7, shared decision-making (SDM) between the patient and clinician regarding cancer therapy considerations and appropriate cardioprotective measures