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Thursday, March 27

8:25am Chairperson's Remarks
Peter Karp, Ph.D., Director, Bioinformatics Research Group, SRI International

8:30 Pathway Tools Software: Overview and Recent Enhancements
Peter D. Karp, Ph.D.
Pathway Tools is a comprehensive environment for modeling the genome, 
metabolic pathways, and regulatory network of an organism. Recent enhancements to Pathway Tools include a visualization of the cellular transcriptional regulatory network, the ability to capture new types of cellular regulation, improved support for electron transport pathways, and analysis of the interface between transport and metabo-lism. It also provides a database repository mechanism for facile sharing of pathway databases.

9:00 MouseCyc: A Curated Biochemical Pathways Database for the Laboratory Mouse
Carol J. Bult, Ph.D., Staff Scientist, Informatics, The Jackson Laboratory
The MouseCyc database represents a significant advance for biomedical researchers wanting to access mouse genetic and genomic data in the context of physiological and cellular processes. The initial focus for the development of MouseCyc is on metabolism and includes such cell level processes as biosynthesis, degra-dation, energy production, and detoxification. MouseCyc differs from existing pathway databases containing mouse pathway data because of the extent to which the information in MouseCyc is integrated with functional, phenotypic, expression and homology data about mouse genes that is available from the Mouse Genome Informatics (MGI; http://www.informatics.jax.org)) database. Examples of the relevance of MouseCyc to better use of the mouse as a model system for understanding human biology and the power of integrating gene-specific knowledge in the context of pathways will be presented.

9:30 Visualization and Integration of Biochemical Pathways at the Saccharomyces Genome Database
Eurie L. Hong, Ph.D., Head Curator, Saccharomyces Genome Database, Stanford University School of Medicine 
S. cerevisiae provides an excellent system for the study of biosynthetic and catabolic pathways and many enzymes involved in these pathways have been identified and characterized. The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org/) displays curated biochemical reactions and pathways as they occur in S. cerevisiae using the Pathway Tools software that is developed and maintained by Peter Karp and his colleagues at SRI International. Its integration with SGD provides access to curated data about the role of genes and their products as well as additional web-based analysis tools. SGD is funded by the US National Human Genome Research Institute.

10:00 Technology Spotlight

Sponsored by

Analysis of HER2/neu as a Diagnostic/Biomarker Using ExPlain丒to Examine Signaling Pathways and Transcription Factors Holger Karas, Senior Vice President, Business Development, BIOBASE GmbH HER2/neu expression levels are a biomarker for qualifying a breast cancer patient for potential response to herceptin. We analyzed gene expression data using ExPlain丒to explore the relationship of transcription processes in the causal basis for HER2/neu expression. This study helps identify potential biomarkers for better treatment with herceptin.

10:15 Technology Spotlight

Sponsored by

Building Disease Models from Transcriptomic, Proteomic, and Metabolomic Data Arthur Okamoto, Ph.D., Senior Product Manager, Ingenuity Over the past few years tremendous technological advances have led to the adoption of transcriptomic, proteomic, and metabolomic platforms across the drug discovery and development process to accelerate biomarker discovery and drug mechanism of action and toxicity efforts. However, life science researchers are now faced with the downstream challenge of analyzing, integrating, and interpreting these large scale datasets in the context of cellular and metabolic processes, and molecular pathways in order to generate testable hypotheses and accelerate the next steps in their research. This presenta-tion will focus on analysis of data from multiple 憃mics platforms using Ingenuity Pathways Analysis in order to elucidate the molecular underpinnings of rat and mouse models of disease and drug response.

10:45 Poster Competition & Refreshment Break in the Exhibit Hall

11:30 Dictyosteleum Pathway Database 
Rex Chisholm, Ph.D., Director, Genetic Medicine, RH Lurie Cancer Center, Northwestern University 
dictyBase is the model organism database for the cellular slime mold Dictyostelium discoideum. It uses genome sequence to organize biological knowledge resulting from experimental studies using this organism. We have used the Pathway Tools software package to help identify and characterize biochemical pathways based on the pres-ence in the genome of genes encoding components of these pathways. This approach is especially valuable for comparative genomics to investigate variations in pathways between different organisms.

12:00pm Biochemical Pathway Databases for Plants
Lukas Mueller, Ph.D., Department of Plant Breeding, Cornell University 
Plants have a rich and diverse biochemical pathway repertoire, which is exploited in many different ways by humans - as foods, medicines, construction materials, and biofuels. Over the past few years, a number of biochemical pathway databases for plants have been generated, such as AraCyc (Arabidopsis thaliana), RiceCyc (Rice), MedicCyc (Medicago truncatula), and LycoCyc (tomato). Ongoing and past efforts to improve the annotation of plant pathways into MetaCyc have resulted in representation of plant pathways in these databases, which are continually annotated and curated.

LUNCHEON TECHNOLOGY WORKSHOP

12:30 Presentation I Sponsored by Qiagen 1:00 Presentation II (Sponsorship Available)

1:30 Break

1:45 Chairperson's Remarks
Carl L. Alden, Ph.D., Vice President, Preclinical Development & Drug Safety Evaluation, Millennium Pharmaceuticals, Inc. (invited)

1:50 Integration of Novel Technologies in Discovery and Early Development Toxicology 
Eric A. G. Blomme, D.V.M., Ph.D., Diplomate A.C.V.P., Project Leader, Abbott Laboratories 
Toxicity represents an important cause of failure in the late stages of discovery and preclinical development. Therefore, early identification of the toxic liabilities of experimental compounds represents one of the most promising alternatives to decrease overall R&D costs. In this presentation, we will review our current Discovery toxicology strategy that leverages several new methodologies in an effort to characterize the toxico-logic profile of compounds at early stages. Using specific examples, we will illustrate how this approach can be successfully implemented in a discovery or preclinical organization.

2:20 A Lead Optimization and Early Development Toxicology Strategy Specific to Novel Oncology Targets 
Carl L. Alden, Ph.D., Vice President, Preclinical Development & Drug Safety Evaluation, Millennium Pharmaceuticals 
Discovery stage and early nonclinical development toxicology studies in the oncology therapeutic area present unique challenges in predicting for success in the clinic, relative to adverse effects. The attrition rate in oncology development is over 90%, often because of toxicity. Frequently, what is termed failed efficacy is actually a consequence of lack of tumor specificity for the therapeutic target. The challenge to the discovery & early development stage toxicologist is amplified for novel targets in oncology. A strategy to avoid progressing molecules with chemical structure based adverse effects while refining the understanding of the tumor specificity and the PK/PD/toxicity relationships across species, specific to novel oncology therapeutic candidates, will be the focus of this presentation. 

2:50 Predictive Value of in Vitro Safety Studies 
Willi Suter, Ph.D., Unit Head, Genetic Toxicology and Safety Pharmacology, SP&A, Novartis Pharma AG 
The predictivity of in vitro methods and their importance for decision-making in drug development is shown for four important areas of pharmaceutical safety evaluations, i.e. genetic toxicology, safety pharmacology, phototoxicity and organ toxic-ity. A comprehensive analysis of the predictivity of genetic toxicity tests for rodent carcinogenicity revealed a major problem with the specificity of the in vitro mammalian cell assays, which indicates the risk that efficacious drug candidates might have been dropped because of false positive in vitro results. Therefore, data from in vitro studies, including the recently introduced hERG channel inhibition test to predict QT interval prolongation and from the in vitro 3T3 NRU phototoxicity test to predict phototoxicity should be used with great care for decision-making. In vitro organ toxicity models provide important mechanistic information. The information obtained from in vitro models has significantly improved the safety of patients in clinical studies, since there is much more data available early in the development process.

3:20 Plenary Keynote 

4:00 Ice Cream Refreshment Break in the Exhibit Hall with BEST OF SHOW AWARDS

4:45 Strategies for Early Toxicity Testing with Focus on Genotoxicity Evaluations
Michael J. Schlosser, Ph.D., D.A.B.T., President and Founder of Midwest BioResearch (MBR) 
There is a wide array of new screening tools available to toxicologists, but the use of a particular screen must be decided carefully to optimize the success of a drug program. Although rapid throughput genetic toxicity screens that require minimal amounts of compound are available during lead optimization, their value for predicting regula-tory outcome is dependent on the specific screen chosen. Screens that mimic the ICH genotoxicity testing battery are best at predicting IND success and will need to keep pace with possible changes in ICH guidelines to maintain predictive value. Regulatory-based genotoxicity screening technologies are also useful in supporting the safety of metabolites, impurities and degradation products when only minimal amounts of these materials are available. Several examples of regulatory-based genotoxicity screening strategies, includ-ing SAR techniques, will be presented.

5:15 Speaker to Be Determined 

5:45 End of Day