By Steve Goldstein
It wasn’t long ago when the idea of tailoring drug therapy based on a patient’s genetic makeup or distinguishing which drug might be most effective in battling a person’s cancer would be relegated to the pages of a science fiction novel. But today, it’s called science. Pharmacogenomics (PGx) to be exact. The marriage of pharmacology and genetics is a union that spawns research aimed at personalizing drug therapies and being able to predict drug responses based on a patient’s genetic makeup.
In addition to reducing life-threatening adverse reactions to drugs, genetic testing itself may also be predictive of treatment failure or success.
“All medications will be designer drugs someday,” said Travis O’Brien, director of the pharmacogenomics program and associate research professor of pharmacology and physiology in GW’s School of Medicine and Health Sciences. “PGx will be another tool in the armamentarium in battling disease.”
In 2005, in conjunction with Shenandoah University’s Bernard J. Dunn School of Pharmacy, SMHS began offering the nation’s first bachelor’s degree in PGx. Courses are primarily held at GW’s Virginia Science and Technology Campus in Ashburn, Va., and can lead to either a bachelor’s degree in health science with a concentration in pharmacogenomics or a Bachelor of Health Science/Doctor of Pharmacy dual degree.
Dr. O’Brien said the goal of the program is to educate a new generation of health sciences graduates “who are acutely aware of the interface between human genetic variability and drug action, as well as the role that genomics can play in identifying biomarkers for disease and targets for therapy.”
Students in the program participate in the groundbreaking research led by Dr. O’Brien, who received his doctorate in toxicology from the University of Cincinnati College of Medicine. One study looks at the drug Warfarin, an oral anticoagulant typically given to patients at risk of stroke, deep vein thrombosis or other types of cardiovascular disease. Though Warfarin is prescribed millions of times each year, the drug is difficult to manage. It inhibits a key gene that promotes clotting, and it’s also deactivated by a liver enzyme. In patients who inherit a genetic variation in that enzyme that slows their metabolisms, Warfarin gets broken down at a slower rate. This variation might cause the drug to stay in the body longer and increase the chances of negative side effects like bleeding.
Dr. O’Brien’s research team, which includes April Barbour, associate professor of medicine at SMHS, and Arthur Harralson, of Shenandoah University, focuses on drug metabolism in African Americans. While there are known genes that affect the metabolism of the anticoagulant Warfarin in Caucasians, those that affect metabolism in minorities are not well-defined.
“Warfarin has a narrow therapeutic window and its metabolism is affected by many factors, including genetic variation,” said Dr. Barbour. “Knowing genetic information helps physicians initially choose the proper dose of Warfarin and then manage patients over time. This has the potential to reduce morbidity and mortality.”
The study is still in the recruitment phase, which Dr. O’Brien expects to complete by the end of the year. DNA will be collected from study subjects and then isolated and analyzed at the PGx program lab in Ashburn, where the samples will be subjected to DNA sequencing. Dr. O’Brien said such research can reduce health care costs “and work as a preventative measure to decrease the incidence of adverse drug reactions associated with Warfarin.”
“There’s probably no other drug in the world that has genetic information that’s so well-linked to the dose someone is receiving,” he said.
A second area of research is in reproductive endocrinology. Along with Paul Gindoff, professor of obstetrics and gynecology at SMHS and director of GW’s Fertility and In Vetro Fertilization (IVF) Center, Dr. O’Brien is examining genetic biomarkers in different populations to find a model that can predict how women will respond to ovarian stimulation therapy. Virtually all women undergoing fertility treatments receive such therapy; nearly 10 percent of them suffer from moderate to severe Ovarian Hyper Stimulation Syndrome (OHSS), a condition that can lead to complications such as ovarian torsion, ovarian rupture and thrombophlebitis.
“This model will help patients decide whether they want to undergo the therapy and help physicians decide how to treat patients who respond poorly to it,” said Dr. O’Brien.
A second phase of the research is a case-control study that examines blood samples from patients who have had OHSS and compares them to those who responded normally. If the latter is found to have a different genotype than those who experienced toxicity, “you could create a simple genetic test that will let a woman know whether she’s at risk of over-stimulating,” Dr. O’Brien said.
Dr. Gindoff called the research a potential “grand slam.” In the future, predicting who is at risk to develop OHSS “will save a lot of people angst and medical treatment because we can be sure to treat them more appropriately.” It might also indirectly increase the success rate of IVF because the procedure could be performed safely in more cases.
Dr. O’Brien is also excited by the prospect of targeting cancer with genetically tailored medications. Since cancers are typically diagnosed with a biopsy, physicians might be able to use those tissue samples to study the DNA of the cells. This technique could lead to selecting a drug and dosage that is most suitable for combating each patient’s specific form of cancer.
“One person’s liver cancer is not the same as another’s,” he said. “With better understanding of these variances, we will be able to treat cancers differently, and that’s a major area where genetics research will have a big impact.”
Dr. O’Brien hopes that the PGx program will help to shape how future health care professionals think about and treat their patients. Joseph Bocchino, interim senior associate dean for health sciences, said that pharmacogenomics “specifically moves us closer to being able to treat a patient as an individual human being, as opposed to taking the results from a clinical trial with 5,000 subjects and treating an entire universe of people.”
Currently, the program has 16 students. But Dr. Bocchino suspects it will expand.
“If I was talking to a high school graduate, I would say that this program offers multiple pathways to science, the retail pharmacy business and industry,” he said.
For years, physicians have spoken about providing personalized medicine, but the reality was mainly restricted to diet, age, lifestyle and health status. Dr. O’Brien believes that pharmacogenomics has the potential to truly realize the promise of the field.
“It’s the ability to take genetic information and apply it to patient care,” he said, “which ultimately will lead to better health care overall.”