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  1. Advancing Regulatory Science

Role of Genomic Ancestry in Tyrosine Kinase Inhibitor (TKI)-Induced Cardiotoxicity

CERSI Collaborators: Stanford University: Joseph C. Wu, MD, PhD; Mark Mercola, PhD; Ronald Witteles, MD

FDA Collaborators: : Center for Drug Evaluation and Research: Laleh Amiri-Kordestani, MD; Kevin Ford, PhD; Margret Merino, MD

Project Start Date: August 2022

Regulatory Science Challenge

Cancer and cardiovascular disease are the leading causes of mortality both in the United States and globally. Many cancer survivors develop cardiovascular diseases as a consequence of successful anticancer treatment. Among the anticancer treatments with detrimental cardiac side effects, the drug class of tyrosine kinase inhibitors (TKI) has been increasingly reported to cause severe cardiovascular problems in patients using them. Data show that underrepresented minorities are predisposed to developing cardiovascular disease as a consequence of the anticancer TKI treatment. In particular, Black patients are three times more likely than white patients to develop cardiotoxicities as a consequence of anticancer treatment, but the biological mechanism for these differences have not been studied in detail.

Project Description and Goals

In this project, investigators aim to study the genetic background differences among patients in the development of cardiovascular disease as a consequence of anticancer TKI treatment. To perform this study, investigators will use the patient-derived human induced pluripotent stem cell (iPSC) platform. These cells are derived directly from patients, so they carry their unique genome and can be differentiated into any cell type of interest. For this project, investigators will first derive iPSCs from patients with different racial and ethnic backgrounds (Black versus White) and differentiate them into cardiomyocytes. iPSC-derived cardiomyocytes (iPSC-CMs) will then receive anticancer TKI treatment. Functional studies will be performed to see how the cells are affected by the drug and which genes are changed in different patients. Genetic differences between the patients and how they influence their individual susceptibility to cardiovascular side-effects of anticancer TKI will be analyzed. Results from this study may inform consideration of genetic ancestry during drug development and treatment with increased precision, thus improving patient survival and alleviating long-term cardiovascular consequences of anticancer drug treatment.

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