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S10: From “omics” to biomarkers of toxicity
ARTICLE IN PRESS Abstracts / Experimental and Toxicologic Pathology 61 (2009) 257–295
consortium is to assess the value of combining data generated from ‘omics technologies (proteomics, transcriptomics, metabolomics) with the results from more conventional toxicology methods, to facilitate more informed decision making in preclinical safety evaluation. A library of 1900 scanned images was created of full-face sections of liver and kidney tissue specimens from male Wistar rats treated with 16 proprietary and reference compounds of known toxicity; additional biological materials from these treated animals were separately used to create ‘omic data, that will ultimately be used to populate an integrated toxicological database. In respect to assessment of the digital slides, a webenabled digital slide management system, Digital Slide Server (DSS), was employed to enable integration of the digital slide content into the ‘‘omics’’ database and to facilitate remote viewing of digital slides by pathologists connected with the project. DSS also facilitated manual annotation of digital slides by the pathologists, specifically in relation to marking particular toxicological lesions of interest. Tissue microarrays (TMAs) were also constructed from these specimens for the purpose of creating a repository of tissue from animals used in the study with a view to later-stage biomarker assessment. As the PredTox consortium itself aims to identify new biomarkers of toxicity, these TMAs will be a valuable means of validation. In summary, a large repository of toxicological images was created enabling the subsequent pathological analysis of samples through remote viewing and, along with the utilisation of TMA technology, will allow the validation of biomarkers identified by the PredTox consortium. doi: 10.1016/j.etp.2009.02.010
S10 From ‘‘omics’’ to biomarkers of toxicity Angela Mally Department of Toxicology, University of Wu¨rzburg, Wu¨rzburg, Germany The discovery and development of new drugs is very costly and the attrition rate of drug candidates due to late-breaking findings in preclinical safety studies is high. Improved prediction of drug-induced toxicity through development of more sensitive safety biomarkers and better understanding of key mechanisms of toxicity may reduce the cost of preclinical safety evaluation and assist regulatory decision making. There is general agreement that omics technologies combined with statistical tools offer great potential for biomarker
261
discovery by allowing both identification of biological signals related to toxicity and interpretation with respect to regulatory networks and mechanisms. Thus, omics profiling techniques, particularly toxicogenomics, are increasingly being used by pharmaceutical companies to predict or monitor adverse effects and have long made their way into internal decision making. However, the process of qualifying omics-derived exploratory markers as known valid safety biomarkers is more complex and by far exceeds the resources of individual companies. Thus, several collaborative projects involving academic and industrial institutions as well as regulatory agencies have been initiated with the aim of assessing the value of omics in preclinical safety evaluation and delivering tools for improved prediction of toxicity. Various stages of biomarker development and recent advances in establishing new biomarkers will be presented, with an emphasis on novel omics-derived indicators of nephrotoxicity. doi: 10.1016/j.etp.2009.02.011
S11 Morphology of drug-induced hepatotoxicity Luigi Terracciano Department of Pathology, University Hospital Basel, Basel, Switzerland The liver is the major site for drug metabolism. It is not surprising, therefore, that drug toxicity and adverse drug reactions frequently affect the liver. Drug-induced liver disease represents an important problem. More than 1100 drugs have been implicated in causing liver disease at the least on rare occasions. Drug-induced liver injury appears to account for about 10% of hepatitis in adults and more than 40% of cases of hepatitis among patients over 50 years of age. Most forms of drug injury are less common in children compared to adults. Some forms of drug-induced liver disease, however, are more common in children, e.g. valproic and aspirin-induced injury. Up to 25% of cases of fulminat hepatic failure and 20–50% of cases of nonviral chronic hepatitis may be drug induced. Hepatic manifestations of drug-induced liver injury can mimic almost the entire spectrum of liver diseases. The predominant clinical presentations, however, resemble either acute hepatitis (from hepatocellular injury) or cholestatic liver disease. Acute hepatotoxic injuries develop over a relatively short time and show no histopathological features of chronicity. Subacute hepatotoxicity includes damage developing over weeks to
consortium is to assess the value of combining data generated from ‘omics technologies (proteomics, transcriptomics, metabolomics) with the results from more conventional toxicology methods, to facilitate more informed decision making in preclinical safety evaluation. A library of 1900 scanned images was created of full-face sections of liver and kidney tissue specimens from male Wistar rats treated with 16 proprietary and reference compounds of known toxicity; additional biological materials from these treated animals were separately used to create ‘omic data, that will ultimately be used to populate an integrated toxicological database. In respect to assessment of the digital slides, a webenabled digital slide management system, Digital Slide Server (DSS), was employed to enable integration of the digital slide content into the ‘‘omics’’ database and to facilitate remote viewing of digital slides by pathologists connected with the project. DSS also facilitated manual annotation of digital slides by the pathologists, specifically in relation to marking particular toxicological lesions of interest. Tissue microarrays (TMAs) were also constructed from these specimens for the purpose of creating a repository of tissue from animals used in the study with a view to later-stage biomarker assessment. As the PredTox consortium itself aims to identify new biomarkers of toxicity, these TMAs will be a valuable means of validation. In summary, a large repository of toxicological images was created enabling the subsequent pathological analysis of samples through remote viewing and, along with the utilisation of TMA technology, will allow the validation of biomarkers identified by the PredTox consortium. doi: 10.1016/j.etp.2009.02.010
S10 From ‘‘omics’’ to biomarkers of toxicity Angela Mally Department of Toxicology, University of Wu¨rzburg, Wu¨rzburg, Germany The discovery and development of new drugs is very costly and the attrition rate of drug candidates due to late-breaking findings in preclinical safety studies is high. Improved prediction of drug-induced toxicity through development of more sensitive safety biomarkers and better understanding of key mechanisms of toxicity may reduce the cost of preclinical safety evaluation and assist regulatory decision making. There is general agreement that omics technologies combined with statistical tools offer great potential for biomarker
261
discovery by allowing both identification of biological signals related to toxicity and interpretation with respect to regulatory networks and mechanisms. Thus, omics profiling techniques, particularly toxicogenomics, are increasingly being used by pharmaceutical companies to predict or monitor adverse effects and have long made their way into internal decision making. However, the process of qualifying omics-derived exploratory markers as known valid safety biomarkers is more complex and by far exceeds the resources of individual companies. Thus, several collaborative projects involving academic and industrial institutions as well as regulatory agencies have been initiated with the aim of assessing the value of omics in preclinical safety evaluation and delivering tools for improved prediction of toxicity. Various stages of biomarker development and recent advances in establishing new biomarkers will be presented, with an emphasis on novel omics-derived indicators of nephrotoxicity. doi: 10.1016/j.etp.2009.02.011
S11 Morphology of drug-induced hepatotoxicity Luigi Terracciano Department of Pathology, University Hospital Basel, Basel, Switzerland The liver is the major site for drug metabolism. It is not surprising, therefore, that drug toxicity and adverse drug reactions frequently affect the liver. Drug-induced liver disease represents an important problem. More than 1100 drugs have been implicated in causing liver disease at the least on rare occasions. Drug-induced liver injury appears to account for about 10% of hepatitis in adults and more than 40% of cases of hepatitis among patients over 50 years of age. Most forms of drug injury are less common in children compared to adults. Some forms of drug-induced liver disease, however, are more common in children, e.g. valproic and aspirin-induced injury. Up to 25% of cases of fulminat hepatic failure and 20–50% of cases of nonviral chronic hepatitis may be drug induced. Hepatic manifestations of drug-induced liver injury can mimic almost the entire spectrum of liver diseases. The predominant clinical presentations, however, resemble either acute hepatitis (from hepatocellular injury) or cholestatic liver disease. Acute hepatotoxic injuries develop over a relatively short time and show no histopathological features of chronicity. Subacute hepatotoxicity includes damage developing over weeks to