Day Two:

Tuesday, November 16th

7:30-8:15 Breakfast Technology Workshop Sponsored By Safety Biomarker Discovery: Genomic Assessment of Species, Tissue and Disease Specificity Dr. Kellye Daniels, Senior R&D Scientist, Toxicogenomics, Gene Logic, Inc.

8:30-9:10 Reports from ThinkTank Sessions

"Omic" Biomarkers: 
Toxicogenomics, Toxicoproteomics and Metabonomics

9:10-9:15 Chairperson's Opening Remarks
Dr. William Mattes, Senior Scientific Director, Toxicogenomics, Gene Logic, Inc.

9:15-9:45 Analysis of Large-Scale Toxicogenomic Databases
Dr. Hugh Salter, Associate Director, Dept. of Molecular Sciences, AstraZeneca R&D
Large-scale gene expression databases provide a starting point to derive numerical predictive models. A specific aim is to be able to rank and compare a range of different substances for potential toxicity. Different approaches that we have used to model and predict toxicity will be presented. Several different scenarios for how to use models will be discussed

9:45-10:15 Use of Microarrays to Find Biomarkers for Novel Toxicities
Dr. James Stevens, Research Fellow, Toxicology, Eli Lilly and Co.
During drug development, unprecedented and novel toxicities arise. Often, these toxicities are difficult to monitor with existing biomarker strategies. In addition, mechanisms can be obscure, further complicating biomarker discovery and development. Microarrays are an attractive technology, both for elucidating mechanisms and developing lists of candidate gene biomarkers. The presentation will address examples of how microarray technology has been used to discovery new biomarkers and address novel toxicities

10:15-11:00 Coffee Break with Exhibit and Poster Viewing

11:45-12:15 Combining Genomics and Metabonomics to Develop Biomarkers: a Work in Progress
Dr. Jonathon Lyon, Head, Molecular Pathology and Toxicology, GlaxoSmithKline
The advent of metabonomics and genomics has provided an unprecedented opportunity to identify potential biomarkers of toxicity. A case study will be presented detailing how these technologies have been used in concert, often on samples from the same study, to identify and characterize novel tissue, urine and plasma markers of peroxisome proliferation in pre-clinical species. Although there are still significant hurdles to overcome in the transition of these biomarkers to the clinic, some thoughts and work in progress regarding the provision of data to support this will also be discussed.

12:15-12:45 Analyzing Mechanisms of Liver Toxicity Using Transcriptomics, Proteomics and Metabolomics Approaches
Dr. Wilbert Heijne, Study Director Toxicogenomics & Bioinformatics, TNO Nutrition and Food Research
We would like to present results of various studies analyzing (liver) toxicity using transcriptomics, proteomics and metabolomics approaches. Initially we studied changes induced in liver by model hepatotoxicants. Effects were followed in time, depending on the dose levels. Also, mild liver toxicity after exposure to food additives, and non-hepatotoxic chemicals was analyzed. Other studies aim to determine and predict effects of mixtures of (toxic) compounds.

1:15-2:40 Luncheon Technology Workshop
TaqMan Applications in Toxicogenomics/Toxicogenetics
Dr. Katherine D Lazaruk, Mgr, Applied Biosystems

Toxicity Biomarker Validation and Translation

2:40-2:45 Chairperson's Opening Remarks
Dr. Rakesh Dixit, Senior Research Scientist, Safety Assessment, Merck & Co.

2:45-3:15 Validation of In Vitro Toxicity Biomarkers Against Clinical Endpoints
Dr. Vivek Kadambi, Senior Scientist & Associate Director Safety Pharmacology, Discovery Pharmacology Metabolic Disease, Millennium Pharmaceuticals Inc.
In vitro toxicology testing can now be leveraged in early lead optimization to identify genetic toxins, QT liability, and liver toxicity with high precision. For genetic toxicity and QT liability the concordance of results with human response has been confirmed as over 90%. The concordance for liver toxicity using primary rat hepatocyte test system is 75% with 0% false positives; the concordance value based on failure to identify all liver toxins. The database and test system validating these assays will be presented.

3:15-3:45 Clinical Validation of In Vitro Toxicity Biomarkers
Dr. Ramon Mohanlal, Medical Director, Drug Evaluation and Approval, Vertex Pharmaceuticals
New chemical entities are selected on the basis of in vitro screening assays prior to pre-clinical and subsequently clinical in vivo testing. The in vitro readout is often a cell-based signature, which often cannot be obtained in the clinic due to limitations in obtaining end-organ tissue. The usefulness of the in vitro screening assays therefore is determined by their ability to predict in vivo toxicity results. Prospective and retrospective approaches for in vitro/in vivo correlation and validation will be discussed.

3:45-4:15 Interspecies Bridging Safety Biomarkers of Nephrotoxicity
Dr. Rakesh Dixit, Section Head, Toxicokinetics and Biomarkers Laboratories, Safety Assessment, Merck & Co.
Interspecies bridging biomarkers of drug safety that can be measured non-invasively offer the greatest opportunity for predicting and monitoring toxicity in both non-clinical and clinical settings. An ideal biomarker should be reflective of treatment or disease related changes, it should represent high signal to noise ratio, stable in body fluids and finally must be adaptable to analytical assay development. Biomarker needs to be validated both analytically as well as biologically in appropriate animal models or clinical settings. The biological validation needs to be considered on the basis of commonality in toxicity mechanisms irrespective of pharmacological activity, target organ specificity, dose and time-dependent toxicological effects as well as the reversibility of these adverse effects. The presentation will discuss: (1) experimental approaches to qualification of toxicity biomarkers; (2) use of toxicogenomic and metabonomic approaches to discovery and development of new biomarkers of nephrotoxicity; (3) approaches to qualification of safety biomarkers in clinical samples; (4) utility of biomarkers in early discovery, lead optimization and safety assessment.

4:15-4:45 Refreshment Break and Exhibit and Poster Viewing 

4:45-5:30 Case Study: Validation and Translation of Biomarkers of Oxidant Stress 

I. Analytical Validation of Biomarkers of Oxidant Stress
Dr. Leslie Shaw, Professor, Dept. of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center
This presentation will describe the criteria for the development and validation of assays for biomarkers that are incorporated into clinical investigation of new therapies. Following a review of the overall principles involved the focus will be on the development and validation of quantitative HPLC/MS/MS biomarker assays. Included will be examples of the development and the selectivity and sensitivity characteristics of an assay, including a simple sample preparation approach we are currently using for biomarkers of oxidant stress. Challenges in developing robust assays for biomarkers include: (1) quantitation of biomarkers present at relatively high background levels in blank biological matrices; (2) development of a selective assay for analytes subject to selectivity problems using exact mass calibration. Suggested approaches to overcoming these challenges will be described.

II. Clinical Validation of Biomarkers of Oxidant Stress in Disease
Dr. Amin Nanji, Professor, Dept. of Pathology and Laboratory Medicine; and Director, Clinical Chemistry, University of Pennsylvania Medical Center 
It is unclear whether oxidative stress is a primary initiating event or a consequence of the disease process. The evidence for involvement of oxidant stress in various diseases will be presented. Therapeutic agents that inhibit selective targets of oxidant stress should enhance our understanding of the involvement of oxidant stress in various pathological conditions. Examples will be given of studies that support the use of antioxidant compounds in the treatment of disease.

6:00-7:00 Reception in the Exhibit Hall (held jointly with Idiosyncratic Toxicity meeting)

7:00 Close of Conference