Integrating expression-based drug response and SNP-based pharmacogenetic strategies into a single comprehensive pharmacogenomics program

Abstract

In the third millennium, competitive advantage in drug development will derive from expertise in two areas: 1) the ability to prioritize and triage hits from a combinatorial chemistry/high-throughput screening experiment and pursue only those hits most likely to succeed through clinical development, and 2) the ability to identify those patients capable of mounting a therapeutic response with minimal toxic effects. Pharmacogenomics, the branch of genomics addressing molecular pharmacology and toxicology, is anticipated to streamline drug development by addressing these issues. Pharmacogenomics includes two separate disciplines: expression pharmacogenomics and pharmacogenetics. Typically, they are regarded as unique fields and are pursued independently from each other. Here, we describe a pharmacogenomic strategy that combines and integrates both fields to create a single robust program. GeneCalling, a rapid, comprehensive differential transcript expression profiling technique, is applied to rodent models of drug response to identify novel markers predictive of drug efficacy and toxicity. SeqCalling, a high-throughput transcript sequencing strategy with a coding region bias, has identified 120,000 novel human single nucleotide polymorphisms (SNPs). Novel pharmacogenetic candidates are then identified by searching the human orthologs of rodent drug response genes for SeqCalling SNPs that can be pursued in systematic genotype screens to verify clinical correlations. In this manner, GeneCalling expression pharmacogenomics identifies markers capable of triaging leads from hits and SeqCalling converts a subset of these markers into pharmacogenetic correlates capable of identifying appropriately responsive patients. Drug Dev. Res. 49:54–64, 2000. © 2000 Wiley-Liss, Inc.