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Hepatic and Cardiac Toxicity Systems modelling

Final Report Summary - HECATOS (Hepatic and Cardiac Toxicity Systems modelling)

Executive Summary:
HeCaTos (Hepatic and Cardiac Toxicity System modelling, http://www.hecatos.eu) is a five year research and development project part of the European Commission’s Seventh Framework Programme Health. The HeCaToS consortium, a private-public partnership composed of 14 Academics, SMEs and LEs, set out to respond to the challenge posed by Francis Collins et al in Science (2008) who proposed the bypassing of animal-based human safety testing, by shifting toxicology to a predominantly predictive science focused on broad inclusion of target-specific, mechanism-based, biological observations in vitro.

Key is to develop bioactivity profiles that are predictive of human disease phenotypes, by identifying signalling pathways which, when perturbed, lead to toxicities. This mechanistic information is then to be used for iteratively developing computational models that can simulate the kinetics and dynamics of toxic perturbations of pivotal signalling pathways, ultimately leading to systems models which can be applied as in silico predictors for human drug safety. Consequently, the main objective of HeCaToS has been: to model, by combining recent advances in computational chemistry and systems biology and systems toxicology, toxic perturbations in the liver and in the heart across multiple scales, from molecular interactions, through macromolecules, to (sub-)cellular functionalities and organ physiologies, and even the intact human being.
For this, advanced human 3D multi-cell-type liver and heart assays have been put in place. In parallel, for benchmarking results in vitro against the human situation in vivo, heart resp. liver biopsies have been obtained from patient suffering from heart, resp. liver injury because of treatment with particular toxic drugs. In vitro assays have been challenged with the same drugs, at physiologically relevant (therapeutic and IC20) doses in 14 days repeated dose treatment regimes. Multiple analytical ‘omics platforms have been applied to generate epigenomics, transcriptomics, proteomics and metabolomics data across dose and time, in combination with functional assays which specifically monitored mitochondrial performance during toxic treatment. Cross-omics data were integrated using a range of bioinformatics/mathematical/statistical methods, and information on perturbed signalling pathways was retrieved using the ConsensusPathdB resource. Results were applied to populate computerized models for predicting myocardial dysfunctioning, resp. liver necrotic and cholestatic events.

All planned in vitro/in vivo samples have been generated, and all cross-omics and functional analyses have been finalized in due time. Using these results, the consortium successfully developed an integrated computational approach consisting of dynamic time series analysis, protein network propagation and modelling of myocardial, resp. hepatic functions. We were also able to use this approach for identifying candidate biomarkers of target organ toxicity in vitro and for demonstrating clinical transferability of these biomarkersin drug-treated patients presenting the relevant toxic phenotype.

The HeCaToS project has in general been able to accumulate very large data sets which allow for multiple innovative data analysis approaches thereby advancing our knowledge on the bioinformatics of cross-omics analysis, and consequently, our insights in the complexity of biology. Data analysis efforts will therefore be continued in the years to come.

In summary, we present the hitherto most comprehensive study on heart and liver toxicity at multi-omics levels thereby also showing the relevance of exploiting well-designed human cell models in combination with physiological dosing for reliably predicting human toxicity in vivo, along with a reproducible workflow for pre-clinical analysis of adverse drug responses from complex genomic data.
The HeCaToS consortium has managed to share its main findings with representatives from the major regulatory authorities, namely the European Medicines Agency, the European Food Safety Authority and the OECD.
Project Context and Objectives:
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Project Results:
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Potential Impact:
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List of Websites:
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