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Day One:
Monday, November 15th
12:00-1:00 Conference Registration
1:00-1:10 Welcoming Remarks from Conference Director
Biomarkers of Organ- or Mechanism-Specific Toxicity
1:10-1:15 Chairperson's Opening Remarks
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Nephrotoxicity |
1:15-1:45 Use of Protein-Based Biomarkers in Nephrotoxicity Studies
Dr Graham Betton, Senior Principal Scientist, Safety Assessment, AstraZeneca Pharmaceuticals
Toxicology studies typically measure kidney weight, histopathology, plasma urea/BUN and creatinine and urine volume, specific gravity, protein, glucose, electrolytes and some enzyme markers derived from the nephron. Unfortunately these can lack sensitivity, only being elevated in established target organ damage e.g. urea, electrolytes. Other markers only identify lesions of the proximal tubule (AKP, glucose). Because nephrotoxicants which damage other regions of the nephron, e.g. the renal papilla, cannot be detected early by current biomarkers, a set of protein biomarkers have been investigated for nephron segment specificity by immunohistochemistry and for utility as a urinary (non-invasive) biomarkers. These have been complemented with proteomic and metabonomic analysis of urine to provide a holistic approach for the discovery and validation of novel biomarkers of
nephrotoxicity. |
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Hepatotoxicity |
1:45-2:15 Towards Quantitative Predictions of Hepatotoxicity Using Gene Expression Profiles
Dr. Yi Yang, Senior Research Cellular and Molecular Biologist, Abbott Laboratories
Despite improved toxicology testing, hepatotoxicity associated with new drug candidates remains a major hurdle in drug discovery. Recent advances in microarray technology have provided a relatively high throughput tool to monitor toxicity responses on a genome scale. At our laboratories, we have developed a quantitative approach to predict hepatotoxicity based on a compendium of gene expression profiles from hepatotoxic and non-hepatotoxic compounds. This presentation will highlight some of the workflow processes involving gene marker identification and model development.
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Cardiac Toxicity |
2:15-2:45 Evaluation of Troponin Protein As a Biomarker in Preclinical Studies for Drug-Induced Cardiac Injury
Dr. Xiao Feng, Sr. Scientist, Preclinical Drug Evaluation, Johnson & Johnson Pharmaceutical Research and Development
L.L.C.After an exhaustive two-year assessment, the Cardiotoxicity Expert Working Group of the FDA has concluded that the cardiac troponina are the preferred biomarkers for use in preclinical investigations of drug-induced cardiac toxicity. The cardiac troponins I (cTnI) and T (cTnT) are considered to be more sensitive and specific for cardiac injury than all other currently employed serum proteins, such as creatinine kinase, used as bioindicators of cardiac injury. Monitoring the change of cTnI and cTnT in preclinical species is expected to provide new insights on the mechanism of drug induced cardiac toxicity.
2:45-3:45 Refreshment Break with Exhibit and Poster Viewing |
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New Technology showcase
3:45-4:00
Histologically Defined Specific Biomarkers in Drug Development
Martin C. Shaw B.Sc., Senior Scientific Officer, Biotrin International
4:00-4:30 Technology Short Talks
Sponsorship Available (Please contact Arnie Wolfson at 781-972-5431 or
awolfson@healthtech.com)
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Neurotoxicity |
4:30-5:00 GFAP and Related Glial Proteins as Biomarkers of Neurotoxicity
Dr. James O'Callaghan, Distinguished Consultant, Molecular Neurotoxicology, Centers for Disease Control and Prevention
Diverse neurotoxic insults result in hypertrophy of astrocytes at sites of damage to the CNS. The hallmark of this response is enhanced expression of the major intermediate filament protein of astrocytes, GFAP. These observations suggest that GFAP may be a useful biomarker of neurotoxicity. To investigate this possibility, we administered prototype drug and chemical neurotoxicants to experimental animals and assessed the effects of these agents on the tissue content of GFAP using a high throughput robotically-assisted ELISA. Our finding indicate that GFAP is a sensitive and specific biomarker of
neurotoxicity. |
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Genotoxicity |
5:00-5:30 Toxicogenomic Analysis of Gene Expression: an Emerging Approach for Differentiating Genotoxic Mechanisms
Dr. Jiri Aubrecht, Principal Research Scientist, Safety Sciences, Pfizer, Inc.
Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Since gaining an insight into genotoxic mechanisms, i.e., differentiation of DNA-reactive vs. DNA non-reactive, is essential for risk assessment to humans, we investigated whether gene expression profiles can differentiate mechanisms of genotoxicity. Our results indicate the potential utility of toxicogenomics for elucidating mechanism of action of genotoxic agents. |
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Carcinogenicity |
5:30-6:00 Characteristic Expression Profiles Induced by Carcinogens in Rat Liver
Dr. Hans J. Ahr, Vice President, Molecular and Genetic Toxicology, Bayer HealthCare AG.
Application of gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may vice versa allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the two year rat bioassay deregulate characteristic sets of genes in a short term in vivo study in rats for up to 14 days. Based on an initial mechanistic analysis it became evident, that common gene expression responses may exist, which are founded on well defined functional gene categories and may differentiate genotoxic from non-genotoxic carcinogens. By statistical methods discriminating marker genes were then extracted and evaluated for their value to classify genotoxic versus non-genotoxic carcinogens. |
6:00-7:00 ThinkTank Session
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