Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology

Nair, Pooja; Prado, Maricela; Perea‐Gil, Isaac; Karakikes, Ioannis

doi:10.1002/sctm.18-0279

Cited by 6 publications

(6 citation statements)

References 106 publications

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“…Whether these cardioprotective ligands interfere with the anti-tumor effect of the chemotherapeutics should be studied as well. The human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), iPSC-CM-derived 3D cultures and organoids provide human-based model systems to explore the molecular mechanisms of cardiotoxicity and cardioprotection (194). They may also serve as a platform for personalized medicine.…”

Section: Discussionmentioning

confidence: 99%

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments

Audebrand

Désaubry

Nebigil

2020

Front. Cardiovasc. Med.

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Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic. Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory. Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol. We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments

Audebrand

Désaubry

Nebigil

2020

Front. Cardiovasc. Med.

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“…hiPSC‐CMs have provided novel insights for the study of genetic heart diseases and drug responses. 18 , 19 , 20 Patient‐specific hiPSC‐CMs have also been used for pharmacogenetic studies to facilitate the identification of cancer survivors with increased risk of chemotherapy‐related cardiomyopathy. 21 …”

mentioning

confidence: 99%

Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Forghani

Rashid

Sun

et al. 2021

JAHA

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Background Anticancer therapies have significantly improved patient outcomes; however, cardiac side effects from cancer therapies remain a significant challenge. Cardiotoxicity following treatment with proteasome inhibitors such as carfilzomib is known in clinical settings, but the underlying mechanisms have not been fully elucidated. Methods and Results Using human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) as a cell model for drug‐induced cytotoxicity in combination with traction force microscopy, functional assessments, high‐throughput imaging, and comprehensive omic analyses, we examined the molecular mechanisms involved in structural and functional alterations induced by carfilzomib in hiPSC‐CMs. Following the treatment of hiPSC‐CMs with carfilzomib at 0.01 to 10 µmol/L, we observed a concentration‐dependent increase in carfilzomib‐induced toxicity and corresponding morphological, structural, and functional changes. Carfilzomib treatment reduced mitochondrial membrane potential, ATP production, and mitochondrial oxidative respiration and increased mitochondrial oxidative stress. In addition, carfilzomib treatment affected contractility of hiPSC‐CMs in 3‐dimensional microtissues. At a single cell level, carfilzomib treatment impaired Ca 2+ transients and reduced integrin‐mediated traction forces as detected by piconewton tension sensors. Transcriptomic and proteomic analyses revealed that carfilzomib treatment downregulated the expression of genes involved in extracellular matrices, integrin complex, and cardiac contraction, and upregulated stress responsive proteins including heat shock proteins. Conclusions Carfilzomib treatment causes deleterious changes in cellular and functional characteristics of hiPSC‐CMs. Insights into these changes could be gained from the changes in the expression of genes and proteins identified from our omic analyses.

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“… How could hiPSCs be used in future research? Anthracycline drugs Doxorubicin Epirubicin Daunorubicin □ Breast cancer, lymphoma/leukemia, lung cancer, sarcoma, ovarian cancer, gastric cancer, liver cancer, thyroid cancer [ 71 ] □ Recapitulate individual patients’ predilection to cardiotoxicity [ 72 ] □ Assessing effects of acute and chronic toxicity [ 73 ] □ Is it possible to predict which patients will develop cardiotoxicity? □ What cellular changes are observed in CM after exposure?…”

Section: Modeling Anthracyclinesmentioning

confidence: 99%

“…□ What cellular changes are observed in CM after exposure? □ HiPSC-CM derived from breast cancer patients are sensitive to doxorubicin toxicity □ Micromolar concentrations are needed to affect electrical activity, but nanomolecular concentration affect cell viability and cause mitochondrial disturbances □ Identify and verify the genetic basis and molecular mechanisms of cardiotoxicity □ Screen chemicals for potential cardiotoxicity Tyrosine kinase inhibitors Imatinib Sunitinib □ Renal cell cancer, thyroid cancer, breast cancer, leukemia, sarcoma [ 71 ] □ Screen for cardiovascular toxicities [ 74 ] □ Study the mechanism of sunitinib cardiotoxicity [ 75 ] □ Will measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling allow screening of TKIs for cardiotoxicity? □ What is the mechanism of sunitinib-mediated cardiotoxicity?…”

Section: Modeling Anthracyclinesmentioning

confidence: 99%

“…□ What is the mechanism of sunitinib-mediated cardiotoxicity? □ VEGFR2/PDGFR-inhibiting TKIs induce cardiotoxicity in hiPSC-CMs at clinically relevant concentrations □ Sunitinib-mediated toxicity is secondary to multiple kinase inhibition and not only AMPK and RSK □ Determine ways to alleviate cardiotoxicity □ Investigate potential molecular mechanisms underlying drug-induced cardiotoxicity Human epidermal growth factor receptor (HER2) antibodies or inhibitors Trastuzumab Pertuzumab Neratinib □ Breast cancer, gastric cancer [ 71 ] □ Model trastuzumab-related cardiotoxicity [ 76 ] □ Examine the protective role of HER2 modulation [ 77 ] □ What is the mechanism of trastuzumab-induced cardiotoxicity? □ How does concurrent trastuzumab and doxorubicin use contribute to cardiotoxicity?…”

Section: Modeling Anthracyclinesmentioning

confidence: 99%

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

et al. 2021

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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. Summary 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.

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Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology

Cited by 6 publications

References 106 publications

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments

Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

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

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