21st Century Cardio-Oncology: Identifying Cardiac Safety Signals in the Era of Personalized Medicine

Abstract

Cardiotoxicity is a well-established complication of oncology therapies. Cardiomyopathy resulting from anthracyclines is a classic example. In the past decade, an explosion of novel cancer therapies, often targeted and more specific than traditional therapies, has revolutionized oncology therapy and dramatically changed cancer prognosis. However, some of these therapies have introduced an assortment of cardiovascular (CV) complications. At times, these devastating outcomes have only become apparent after drug approval and have limited the use of potent therapies. There is a growing need for better testing platforms, both for CV toxicity screening, as well as for elucidating mechanisms of cardiotoxicities of approved cancer therapies. This review discusses the utility of nonclinical models (in vitro, in vivo, & in silico) available and highlights recent advancements in modalities like human stem cell-derived cardiomyocytes for developing more comprehensive cardiotoxicity testing and new means of cardioprotection with targeted anticancer therapies.

Keywords: cardio-oncology; cardiotoxicity; nonclinical/preclinical models.

Figure 1

The Need for More Effective Methods of Nonclinical Screening in Cancer Treatment-Related Cardiotoxicities There are numerous in vivo, in vitro, and in silico models that can be used for both nonclinical testing of CV toxicities and follow-up investigations of underlying mechanisms, which can be used to develop cardioprotective therapies. IND = investigational new drug; NDA = new drug application.

Figure 2

Promising Personalized iPSC-CM Model for Assessing Cardiotoxicity Patient-derived somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by using Yamanaka’s cocktail of transcription factors and then robustly differentiated into cardiomyocytes (iPSC-CMs) while retaining the individual’s genetic composition. Drug effects on these cells can be assayed through an expanding repertoire of phenotypic outputs to: 1) address whether there are any CV toxicities; 2) if so, their underlying mechanism; and 3) evaluate for potential cardioprotective agents. CV = cardiovascular.