Systems Biology in Pharmacogenomic Research: The Way to Personalized Prescribing?

Koster, Ellen S.; Rodin, Andréi S.; Raaijmakers, J. A. M.; Zee, Anke‐Hilse Maitland‐van der

doi:10.2217/pgs.09.38

Cited by 20 publications

(14 citation statements)

References 66 publications

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“…The P*3 pathway, and other algorithms might be useful in charting a path forward in systems medicine, particularly if applied to cardio-oncology. Use of such a tool, which leverages systems medicine for prevention and therapy, might also limit the occurrence of post-marketing drug withdrawal owing to adverse drug effects, 137 and a ccelerate adequate treatment and cure.…”

Section: Discussionmentioning

confidence: 99%

“…Precision medicine involves a multidisciplinary approach, integrating basic science and clinical research with patient and outcomes information and, in this case, systems medicine data, with the ultimate goal of personalized systems data-based prescribing. [137][138][139] Indeed, computational models, described as molecular interaction maps, have been created to simulate cancer signalling pathways. 140 Results obtained with this model have been verified in experiments on human cell lines in response to various treatments, with reasonably accurate predictive validity.…”

Section: Development Of Computational Avatarsmentioning

confidence: 99%

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

2015

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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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Section: Discussionmentioning

confidence: 99%

Section: Development Of Computational Avatarsmentioning

confidence: 99%

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

2015

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“…An overview of a systems biology approach to pharmacoge-netics and pharmacogenomics can be found in Koster et al . [8]; Nadeau and Dudley [9] present a useful introduction to the systems biology from the viewpoint of genetics and genomics.…”

Section: Systems Biologymentioning

confidence: 99%

Systems Biology Data Analysis Methodology in Pharmacogenomics

2011

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Pharmacogenetics aims to elucidate the genetic factors underlying the individual’s response to pharmacotherapy. Coupled with the recent (and ongoing) progress in high-throughput genotyping, sequencing and other genomic technologies, pharmacogenetics is rapidly transforming into pharmacogenomics, while pursuing the primary goals of identifying and studying the genetic contribution to drug therapy response and adverse effects, and existing drug characterization and new drug discovery. Accomplishment of both of these goals hinges on gaining a better understanding of the underlying biological systems; however, reverse-engineering biological system models from the massive datasets generated by the large-scale genetic epidemiology studies presents a formidable data analysis challenge. In this article, we review the recent progress made in developing such data analysis methodology within the paradigm of systems biology research that broadly aims to gain a ‘holistic’, or ‘mechanistic’ understanding of biological systems by attempting to capture the entirety of interactions between the components (genetic and otherwise) of the system.

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“…Genetic, pathophysiologic, and environmental factors all contribute to variation in drug response, which is in part due to large interindividual differences in processing xenobiotics via absorption, distribution, and elimination. Significant resources continue to be invested in delineating genetic factors associated with variation in drug disposition, and in turn drug response, with the promise of “personalized medicine” [1-3]. Comparatively less attention has been directed toward non-genetic factors, which are equally important in determining drug response [4], and whose contribution increases with age [5].…”

Section: Introductionmentioning

confidence: 99%

Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

Won¹,

Oberlies²,

Paine³

2010

CDM

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Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as dietary substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given dietary substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-dietary substance interactions appropriately.

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Systems Biology in Pharmacogenomic Research: The Way to Personalized Prescribing?

Cited by 20 publications

References 66 publications

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

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

Systems Biology Data Analysis Methodology in Pharmacogenomics

Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

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