Systems biology approaches to adverse drug effects: the example 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.

Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes

“…Moreover, the serum cTnT and cTnI levels are only raised after cardiac damage or dysfunction had occurred. There is an unmet need for biomarkers that can predict potential cardiotoxicity before the onset of adverse cardiac events57. Our data show that the TNF-related cytokines, in particular TRAIL, could augment doxorubicin-induced cardiotoxicity by engaging the upregulated death receptors on the cardiomyocytes (Fig.…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…Importantly, efforts to achieve both early diagnosis and optimal treatment of disease as well as prevent and mitigate cardiac adverse effects in oncology patients has led to study and potential application of multi-omic disciplines to the field of Cardio-Oncology [7,77]. Genomics, epigenomics, transcriptomics, proteomics, miRNAomics, metabolomics and microbiomics have the potential to more precisely guide the clinical management of these patients [7,78]. The integration of multi-omics with systems biology and incorporating disciplines such as mobile health (mHealth), pharmacogenomics, mathematical and computational modeling is depicted in Figures 2 and 3 and has been well described [7,77,78].…”

“…Genomics, epigenomics, transcriptomics, proteomics, miRNAomics, metabolomics and microbiomics have the potential to more precisely guide the clinical management of these patients [7,78]. The integration of multi-omics with systems biology and incorporating disciplines such as mobile health (mHealth), pharmacogenomics, mathematical and computational modeling is depicted in Figures 2 and 3 and has been well described [7,77,78]. poor metabolizer phenotype and CYP2D6 metabolizes up to 20% of medications currently in use in the general population [16].…”

“…P3, Prevent: Prevention is proactively adjusting patients' treatment plans based on their cardiovascular toxicity risk to prevent de novo damage or mitigate further damage from antineoplastic therapy. Adapted with permission [78]. CYP450 = cytochrome P450; EHR = electronic health record.…”

Induction of G2M Arrest by Flavokawain A, A Kava Chalcone, Increases the Responsiveness of HER2 Overexpressing Breast Cancer Cells to Herceptin

“…However, development of resistance to Herceptin is common and the treatment is associated with cardiac dysfunction in 2-7% of cases [32]. Therefore, there is a need for a novel agent that can improve both the efficacy and safety of Herceptin treatment through combination.…”