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  • Review Article
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Systems biology approaches to adverse drug effects: the example of cardio-oncology

Nature Reviews Clinical Oncology volume 12, pages 718–731 (2015)Cite this article

Subjects

Key Points

  • Findings from 'systems biology' approaches that merge technology from life sciences, engineering, computer science, natural sciences and mathematics have elucidated adverse drug effects from a cellular to whole-organism level

  • Systems biology approaches hold promise for chemotherapy-induced cardiotoxicity, which has received increasing attention following improvements in long-term survival of patients with cancer, resulting in the new discipline of cardio-oncology

  • Patients receiving chemotherapy have marked inter-individual variations in cardiotoxicity risk beyond pre-existing cardiovascular disease and its risk factors, indicating an influence of genetic factors

  • Genetic variants that predispose to anthracycline-induced cardiotoxicity, including genes involved in drug transport and metabolism, energy utilization, oxidative stress, apoptosis and cytoskeletal regulation are the best characterized genetic influences

  • Incorporation of genetic signatures, protein biomarkers and mathematical models for the development of new risk prediction tools and therapeutic targets could reduce the extent of chemotherapy induced cardiotoxicity

  • Defining patients' specific predispositions, in order to individualize treatment strategies and thus yield the greatest treatment benefits at the lowest possible cardiotoxicity risk, is the ultimate goal of cardio-oncology

Abstract

Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence of cardio-oncology (or onco-cardiology), which focuses on screening, monitoring and treatment of patients with cardiovascular dysfunctions resulting from chemotherapy. Anthracyclines, such as doxorubicin, and HER2 inhibitors, such as trastuzumab, both have cardiotoxic effects. The biological rationale, mechanisms of action and cardiotoxicity profiles of these two classes of drugs, however, are completely different, suggesting that cardiotoxic effects can occur in a range of different ways. Advances in genomics and proteomics have implicated several genomic variants and biological pathways that can influence the susceptibility to cardiotoxicity from these, and other drugs. Established pathways include multidrug resistance proteins, energy utilization pathways, oxidative stress, cytoskeletal regulation and apoptosis. Gene-expression profiles that have revealed perturbed pathways have vastly increased our knowledge of the complex processes involved in crosstalk between tumours and cardiac function. Utilization of mathematical and computational modelling can complement pharmacogenomics and improve individual patient outcomes. Such endeavours should enable identification of variations in cardiotoxicity, particularly in those patients who are at risk of not recovering, even with the institution of cardioprotective therapy. The application of systems biology holds substantial potential to advance our understanding of chemotherapy-induced cardiotoxicity.

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Figure 1: Candidate genes implicated in doxorubicin-induced cardiotoxicity.
Figure 2: Doxorubicin-induced cardiotoxicity is mediated by TOP2B.
Figure 3: Overlapping tyrosine kinase signalling pathways in anthracycline-induced toxicity.
Figure 4: ABCB1 allele linkage disequilibrium feedforward loops.
Figure 5: The P*3 approach to systems medicine.

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Acknowledgements

We are grateful to Dr Iftikhar Kullo of the Mayo Clinic, Rochester, MN, for editing an earlier version of this manuscript and assistance with figure procurement. We also acknowledge the assistance of Dr Shameer Khader of the Department of Genetics and Genomic Sciences at Mount Sinai Hospital in New York (and formerly of Mayo Clinic in Rochester, MN) for initial discussions before preparation, and for reading an earlier version of this manuscript.

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Authors and Affiliations

  1. Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Sherry-Ann Brown

  2. Division of General Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Nicole Sandhu

  3. Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Joerg Herrmann

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  1. Sherry-Ann Brown
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  2. Nicole Sandhu
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  3. Joerg Herrmann
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Contributions

S.-A.B. and J.H. researched data for this article, all authors made a substantial contribution to discussions of content, S.-A.B. and J.H. wrote the manuscript, and all authors made a substantial contribution to editing and reviewing the manuscript before submission.

Corresponding author

Correspondence to Joerg Herrmann.

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The authors declare no competing financial interests.

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Supplementary Figure 1

Mathematical modelling can be used to predict the occurrence of doxorubicin-induced cardiotoxicity based on dose accumulation. (DOCX 214 kb)

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Brown, SA., Sandhu, N. & Herrmann, J. Systems biology approaches to adverse drug effects: the example of cardio-oncology. Nat Rev Clin Oncol 12, 718–731 (2015). https://doi.org/10.1038/nrclinonc.2015.168

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