Personalized Medicine: Dream or Reality?

Experts define personalized medicine in different ways. Some take the genetic angle, others genomic or proteomic. But no matter what the approach, personalized medicine is buzzworthy. And it seems, regardless of how it is defined, personalized medicine has become the raison d’être for both established and emerging pharma-biotech companies alike.

“Personalized medicine involves the use of information on an individual’s genetic makeup to design strategies for diagnosis, treatment, and prevention of whatever disease you are interested in,” says Richard Zhao, PhD, associate professor of pathology, microbiology, immunology, and human virology and division head of molecular pathology at The University of Maryland School of Medicine in Baltimore.

However, the idea that our genes dictate our response to a certain drug is not new. In fact, it’s been almost 40 years since the publication of a set of classic Lancet papers in which differential drug clearance in monozygotic and dizygotic twins suggested a genetic component to drug responsiveness. These classic papers laid the groundwork for today’s pharmacogenetic and pharmacogenomic studies.

Although the conceptual framework was laid out for researchers, it took nearly all of those 40 years for the technology to catch up to prove the principle of personalized medicine. In fact, during those years, genetic testing has changed so dramatically that we’ve gone from genetics-based twin studies to genotyping. Add to that, the fact that high-throughput genetic screening tests can examine 30,000 genes—and even greater numbers of polymorphic markers—on thousands of patients in one test run and produce results within hours.

Personalized examples

Despite this surge in technology, there haven’t been many examples of personalized medicine. The most developed example in oncology is the normal inactivation of 6-mercaptopurine (6-MP) by thiopurine-S-methyltransferase (TPMT), which was first described in 1980. Individuals with a defective TPMT allelle cannot inactivate 6-MP, causing toxic levels of the drug to accumulate in the blood. Currently, the US Food and Drug Administration (FDA) recommends that before taking 6-MP, individuals undergo a genotyping test for TPMT (which can detect the defective allele) to prevent such toxicity.

Another example of personalized medicine in oncology is irinotecan. This drug is inactivated by the enzyme UGT1A1. The gene promoter for this enzyme is polymorphic, and some alleles produce a nonfunctional enzyme that cannot inactive irinotecan. The drug is, therefore, more toxic to individuals carrying this allele.

“The actual [product insert] for irinotecan now recommends pharmacogenetic testing to determine a patient’s responsiveness to the drug. . . . And that’s a first,” says Stella Davies, MD, PhD, professor of pediatrics, Cincinnati Children’s Hospital, Cincinnati, Ohio. The FDA-approved method for the measurement of genetic variability in the ugt1A1 promoter is called the Invader UGT1A1 molecular assay.

Another FDA-approved assay, Roche’s Aptuchip CYP450 assay, measures the drug-metabolizing, human liver enzyme CYP450. One immediate application of this assay, Zhao says, is in the treatment of depression. “To treat depression is very difficult, especially with the correct treatment and the correct dosing.”

But the range of a therapeutic index and accurate dosing are more crucial in some areas of medicine than in others. And the importance, Davies says, “depends on what you do and how much risk-benefit there is in dose-tinkering.”

The reality

The hope for personalized medicine is that physicians will not prescribe drugs in the same way to everyone. And although there is a lot of enthusiasm about personalized medicine, the reality is that there have been few drugs with such a significant person-to-person variability in responsiveness as to warrant the creation of a genotyping test for them.

But not everyone measures success of personalized medicine by the number of current applications. “I think that [personalized medicine] is a reality, but its application is currently somewhat limited,” says Davies. “The idea that when you go into your doctor’s office in the next five years, you will have your whole genetic sequence bar-coded and have your drugs assigned according to your bar code is not particularly realistic. But the idea that we will move away from one drug size fits all in some clinical areas is very real.” However, with so few examples of personalized medicine in existence, the question of whether it is realistic or necessary is still a matter for debate.

Davies agrees that “a lot of [personalized medicine] is still theoretical, rather than real-world or practical.” She explains that personalized medicine is mostly in the theoretical stages right now because much of the current data and knowledge on genetic modifiers of drug response has been ascertained in a research setting, not a clinical one.

“We’ve got the technology, but we haven’t yet got the intellectual ability to interpret the data as accurately as we need to . . . but that will come, too,” says Davies. According to Davies, personalized medicine is not being applied on a broad scale right now, but it is certainly being applied in a few fields of medicine, including Davies’ own, hematology and oncology.

“Eventually, personalized medicine will be a mainstay of medicine,” says Zhao. His convictions about personalized medicine are evident by the fact that he often entertains his research donors with the following scenario. “One day when you walk into your doctor’s office, they will draw a drop of blood from your fingertip. Then the doctor will plug the blood into a small gadget, where you can watch the testing unfold on a computer screen. And once the testing is complete, you can see your genetic profile on the computer.” All this will happen, he says, so that when the patient returns to their doctor for medication, the doctor will base the prescribing decision on the patient’s genotype. “That will be the future of medicine,” he says. “Even though this seems like science fiction, it’s not going to be far away.”