The Emerging Field of Pharmacogenomics

Charles R. Cantor,
Chief Scientific Officer, SEQUENOM, Inc.
San Diego, CA USA
CV & Publications

It has been known for decades that individuals differ significantly in their response to medication, and that some of these differences are inherited. Genetic variations have been found that affect drug metabolism, including differences in activation and degradation. These differences provide useful clues to differences in drug efficacy, therapeutic windows, and adverse side reactions. The field of pharmacogenetics encompasses the study and utilization of this knowledge towards improved medical practice. Most of the genetic loci discovered that affect drug action were inferred from a knowledge of the biochemistry of drug action.

Now, with complete human genome sequences available, and vast improvements in our power to associate phenotypic traits with genetic variations, we sit on the cusp of a large series of discoveries that will allow a more rational approach to drug discovery, selection of drugs and therapeutic regimens for patient efficacy, and anticipation of the risk of adverse effects. Here the range of individual genetic variations is broadening from drug metabolism to differences in the actual drug targets themselves. The use of high throughput tools like expression arrays also reveals molecular patterns of the responses to drugs. Some of these expression changes will be useful as surrogate markers for the pathophysiologic states currently used as more traditional measures of drug efficacy and adverse effects. This broad set of new tools has been termed pharmacogenomics. If it lives up to its current promise, the eventual result will be individualized therapy: the right dose at the right time of the right drug for the right patient.

In the field of cancer therapy, individualized medicine is already showing tremendous promise. Several important new anti-tumor agents like Gleevec, Herceptin, and IRESSA are only efficacious for a fraction of patients, and this efficacy can be predicted from the occurrence of somatic mutations in the target pathways of these drugs. It is reasonable to suspect that similar somatic genetic variations will underlie the differences in efficacy of an increasing spectrum of anti-tumor agents. These mutations can serve as a guide to understanding the mechanism of drug action and for more efficient design and clinical testing of additional therapeutic agents.

The future of medicine promises widespread use of drugs linked to companion diagnostic tests. The tests will allow selection of optimal therapies. They also promise to reduce the cost of clinical trials, and the time to market of new drugs, by pre-selecting subsets of patients that have a high probability of positive responses.