Pharmacogenetic and pharmacogenomic discovery strategies

Abstract

Genetic/genomic profiling at a single-patient level is expected to provide critical information for determining inter-individual drug toxicity and potential efficacy in cancer therapy. A better definition of cancer subtypes at a molecular level, may correspondingly complement such pharmacogenetic and pharmacogenomic approaches, for more effective personalized treatments. Current pharmacogenetic/pharmacogenomic strategies are largely based on the identification of known polymorphisms, thus limiting the discovery of novel or rarer genetic variants. Recent improvements in cost and throughput of next generation sequencing (NGS) are now making whole-genome profiling a plausible alternative for clinical procedures. Beyond classical pharmacogenetic/pharmacogenomic traits for drug metabolism, NGS screening programs of cancer genomes may lead to the identification of novel cancer-driving mutations. These may not only constitute novel therapeutic targets, but also effector determinants for metabolic pathways linked to drug metabolism. An additional advantage is that cancer NGS profiling is now leading to discovering targetable mutations, e.g., in glioblastomas and pancreatic cancers, which were originally discovered in other tumor types, thus allowing for effective repurposing of active drugs already on the market.