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.