The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--Pharmaceuticals: An Efficient and Humane Approach to Predictors of Potential Toxic Effects of Drugs

Genomics, Proteomics and Bioinformatics

Daniel Casciano
US Food and Drug Administration

Uthay Ezekiel
Incyte Genomics, Inc.

Emmanuel Petricoin
US Food and Drug Administration

The recent completion of the sequencing of the human genome and the genomes of other eukaryotes are providing, for the first time, the ability to discover and evaluate relevant disease, toxicity, and therapeutic efficacy biomarkers in humans and compare these markers to surrogate rodent, cell line, and other more predictive "in silico" approaches. High throughput technologies such as miniaturized cDNA or SNP arrays allow an investigator to evaluate the effect of a drug on a given system over thousands of gene-based endpoints concomitantly. This wealth of information requires high-end bioinformatics that is lagging in maturity compared to the array/display type of technologies that are being employed at the front end. Moreover, since the actual targets of most licensed therapeutics are proteins and not the genes, the ability to employ proteomic-based endpoints for the understanding of drug toxicity and efficacy is a crucial necessity. Efficiency of translation, post-translational modifications, protein stability, phosphorylation state, protein-protein interactions, and protein DNA-binding affinities are examples of parameters which cannot be studied by DNA and mRNA efforts alone. Protein-based analyses are required to address these questions. Understanding normal cellular processes and the establishment, evolution and progression of disease will require the acquisition of the biologically relevant cells of interest in actual tissue. Furthermore, simply establishing which genes are transcribed and which proteins are then translated in any given cell type will still not provide enough information. Ultimately, it is how these genes and proteins interact with each other as networks of functional units and pathways in cells in real tissue, they themselves linked together in complex environments of many different cell types, which may uncover occult toxicity and identify the appropriate endpoints for efficacy and patient cohorts most likely to respond with the fewest unwanted adverse events.

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