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21st Century Cardio-Oncology

JACC: BASIC TO TRANSLATIONAL SCIENCE
a 2016 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

STATE-OF-THE-ART REVIEW

21st Century Cardio-Oncology

Identifying Cardiac Safety Signals in the Era of Personalized Medicine

VOL. 1, NO. 5, 2016 ISSN 2452-302X http://dx.doi.org/10.1016/j.jacbts.2016.05.008

Calvin Chen Sheng, MD,a,b,c Laleh Amiri-Kordestani, MD,d Todd Palmby, PHD,d Thomas Force, MD,a,b,c Charles C. Hong, MD, PHD,a,e,f Joseph C. Wu, MD, PHD,g,h Kevin Croce, MD, PHD,i Geoffrey Kim, MD,d Javid Moslehi, MDa,b,c

SUMMARY

Cardiotoxicity is a well-established complication of oncology therapies. Cardiomyopathy resulting from anthracy- clines is a classic example. In the past decade, an explosion of novel cancer therapies, often targeted and more specific than conventional therapies, has revolutionized oncology therapy and dramatically changed cancer prog- nosis. 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 and for elucidating mechanisms of cardiotoxicities of approved cancer therapies. This review discusses the utility of available nonclinical models (in vitro, in vivo, and in silico) and highlights recent advancements in modalities like human stem cell-derived cardiomyocytes for developing more comprehensive cardiotoxicity testing and new means of cardio- protection with targeted anticancer therapies. (J Am Coll Cardiol Basic Trans Science 2016;1:386–98) © 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

In the last decade, there has been a paradigm shift in cancer treatment from the use of nonselective cytotoxic agents toward targeted therapies

aimed at cellular pathways that have been hijacked by the cancer (1). Indeed, in 2015, oncology was a nat- ural choice as the initial focus of the U.S. government Precision Medicine Initiative, a $215 million invest- ment for individualized approach to patient care (2).

Conventional cancer therapies like radiation can lead to cardiovascular (CV) toxicities due to direct, nonselective myocardial injury (3). Paradoxically, several of the novel targeted oncology therapies are associated with a wide spectrum of CV complications in humans, which were unanticipated based on nonclinical (also known as “preclinical”) safety studies (4,5). Such discrepancies highlight the

From the aCardiovascular Division, Vanderbilt University School of Medicine, Nashville, Tennessee; bCardio-Oncology Program, Vanderbilt University School of Medicine, Nashville, Tennessee; cVanderbilt-Ingram Cancer Center, Nashville, Tennessee; dCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland; eResearch Medicine, Veterans Af- fairs Tennessee Valley Healthcare System, Nashville, Tennessee; fAccelerating Drug Repurposing Incubator, Vanderbilt Institute for Clinical and Translational Research, Nashville, Tennessee; gCardiovascular Division, Department of Medicine, Stanford Uni- versity School of Medicine, Stanford, California; hStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California; and the iDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. The views expressed in this article do not necessarily represent an official position of U.S. Food and Drug Administration. Dr. Wu has received funding from Sanofi; and sits on the scientific advisory board of Stem Cell Theranostics. Dr. Force has consulted for Ariad and Bristol-Myers Squibb. Dr. Moslehi has consulted for Novartis, Pfizer, Bristol-Myers Squibb, Takeda, Ariad, Acceleron, Vertex, Incyte, Rgenix, and Verastem. Dr. Croce has received funding from Ariad; and has consulted for Ariad, Bristol-Myers Squibb, The Medicines Company, Abbott Vascular, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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