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      Models of Models: A Translational Route for Cancer Treatment and Drug Development

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          Abstract

          Every patient and every disease is different. Each patient therefore requires a personalized treatment approach. For technical reasons, a personalized approach is feasible for treatment strategies such as surgery, but not for drug-based therapy or drug development. The development of individual mechanistic models of the disease process in every patient offers the possibility of attaining truly personalized drug-based therapy and prevention. The concept of virtual clinical trials and the integrated use of in silico, in vitro, and in vivo models in preclinical development could lead to significant gains in efficiency and order of magnitude increases in the cost effectiveness of drug development and approval. We have developed mechanistic computational models of large-scale cellular signal transduction networks for prediction of drug effects and functional responses, based on patient-specific multi-level omics profiles. However, a major barrier to the use of such models in a clinical and developmental context is the reliability of predictions. Here we detail how the approach of using “models of models” has the potential to impact cancer treatment and drug development. We describe the iterative refinement process that leverages the flexibility of experimental systems to generate highly dimensional data, which can be used to train and validate computational model parameters and improve model predictions. In this way, highly optimized computational models with robust predictive capacity can be generated. Such models open up a number of opportunities for cancer drug treatment and development, from enhancing the design of experimental studies, reducing costs, and improving animal welfare, to increasing the translational value of results generated.

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          Most cited references28

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          The evolution of signalling pathways in animal development.

          Despite the bewildering number of cell types and patterns found in the animal kingdom, only a few signalling pathways are required to generate them. Most cell-cell interactions during embryonic development involve the Hedgehog, Wnt, transforming growth factor-beta, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. Looking at how these pathways evolved might provide insights into how a few signalling pathways can generate so much cellular and morphological diversity during the development of individual organisms and the evolution of animal body plans.
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            Clinical and economic burden of adverse drug reactions

            Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits. Randomized controlled trials (RCTs) are the main premarketing methods used to detect and quantify ADRs but these have several limitations, such as limited study sample size and limited heterogeneity due to the exclusion of the frailest patients. In addition, ADRs due to inappropriate medication use occur often in the real world of clinical practice but not in RCTs. Postmarketing drug safety monitoring through pharmacovigilance activities, including mining of spontaneous reporting and carrying out observational prospective cohort or retrospective database studies, allow longer follow-up periods of patients with a much wider range of characteristics, providing valuable means for ADR detection, quantification and where possible reduction, reducing healthcare costs in the process. Overall, pharmacovigilance is aimed at identifying drug safety signals as early as possible, thus minimizing potential clinical and economic consequences of ADRs. The goal of this review is to explore the epidemiology and the costs of ADRs in routine care.
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              • Record: found
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              Systems biology: parameter estimation for biochemical models.

              Mathematical models of biological processes have various applications: to assist in understanding the functioning of a system, to simulate experiments before actually performing them, to study situations that cannot be dealt with experimentally, etc. Some parameters in the model can be directly obtained from experiments or from the literature. Others have to be inferred by comparing model results to experiments. In this minireview, we discuss the identifiability of models, both intrinsic to the model and taking into account the available data. Furthermore, we give an overview of the most frequently used approaches to search the parameter space.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/195684
                URI : http://frontiersin.org/people/u/455216
                URI : http://frontiersin.org/people/u/44089
                URI : http://frontiersin.org/people/u/401536
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                19 September 2017
                2017
                : 7
                : 219
                Affiliations
                [1] 1Alacris Theranostics GmbH , Berlin, Germany
                [2] 2Max Planck Institute for Molecular Genetics , Berlin, Germany
                Author notes

                Edited by: Michael Breitenbach, University of Salzburg, Austria

                Reviewed by: Michael Gerhard Löffler, University of Salzburg, Austria; Hans-Werner Mewes, Technische Universität München, Germany

                *Correspondence: Hans Lehrach, lehrach@ 123456molgen.mpg.de

                Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2017.00219
                5609574
                28971064
                cc3e52f4-0a84-4d17-ae2f-c475a587766e
                Copyright © 2017 Ogilvie, Kovachev, Wierling, Lange and Lehrach.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 June 2017
                : 01 September 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 50, Pages: 7, Words: 5751
                Funding
                Funded by: Horizon 2020 10.13039/501100007601
                Award ID: 686282
                Categories
                Oncology
                Perspective

                Oncology & Radiotherapy
                preclinical models,computational model,mechanistic modeling,genetically engineered mouse models,transgenic mice,model optimization

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