Drugs by Design

Genes determine whose eyes will reflect deep pools of mahogany and whose will shimmer like the sea. Sometimes these DNA segments give bragging rights to kids who’ve inherited the ability to roll their tongues. Yet, genes can also determine which children will develop deadly diseases like cancer and how these young patients will respond to potentially toxic medicines. Unfortunately, without knowing which genes are involved in drug response, predicting how someone will react to certain treatments has been a difficult, if not impossible, task — until now.

Medical revolution

Scientists at St. Jude Children’s Research Hospital are using computer technology and new information about human genes to learn why some children with leukemia can be cured with few side effects while others reap no benefit from identical medications. This emerging field of science called pharmacogenomics could someday allow doctors to use genetic snapshots to determine how each patient will process drugs and how to adjust dosages accordingly.

St. Jude investigators William Evans, PharmD, and Mary Relling, PharmD, are leading some of the world’s first pharmacogenomic studies in children with acute lymphoblastic leukemia (ALL). They hope that individualized medicine will eventually boost ALL’s 80 percent cure rate closer to 100 percent, with children experiencing little or no side effects.

“Ultimately, we want to see drugs used in the most effective way—less toxicity and more efficacy,” says Evans, hospital director-elect and member of Pharmaceutical Sciences.

Although researchers at other institutions now recognize that genetic testing has the potential to revolutionize medicine, Evans and Relling foresaw the benefits almost two decades ago when they opened the first pharmacogenomics research plan for St. Jude patients. “At the time, there were people doing similar research in adults with other diseases, but not for pediatric cancer,” says Relling, Pharmaceutical Sciences chair. “In fact, few people were doing pharmacogenomic studies in cancer at all.”

St. Jude has integrated pharmacogenomic studies in most of its primary and secondary clinical treatment plans. However, Evans and Relling say a medical revolution will occur only after researchers conduct more studies, develop more diagnostic tools and work with lawmakers to ensure patients’ genetic information is not misused.

Goodbye to guesswork

Although more sophisticated than the “take two aspirin and call me in the morning” approach, the current science of selecting and dosing medications largely relies on trial and error, says Evans. “You see what happens when you give a drug to 1,000 adults and come up with an average dose that you give almost everyone,” he says. “This in essence treats every patient as if he or she were the average patient, when of course, few people are.”

For a condition like high blood pressure, a doctor typically begins treatment with one of 10 drugs and adds, subtracts or switches medications based on patient reaction.

“With pharmacogenomics, a patient’s genes could tell you exactly which drug is likely to work best,” Evans says. “You might start with a completely different drug for the next patient.”

For decades, doctors have collected patients’ family medical histories as a surrogate for genetic tests. Pharmacogenomics uses a patient’s genome to provide a more precise report on the drug response that has been inherited from their parents.

By taking the guesswork out of finding successful medications, pharmacogenomics could speed recovery times, expose new targets for medications and lower health care costs—curbing the likelihood of adverse drug reactions, which account for 100,000 deaths and 2.2 million hospitalizations in the United States each year.

For children with leukemia, it could mean that the harshest treatments are reserved for only those whose bodies can tolerate them and whose diseases need them. For some St. Jude patients, this has meant the difference between life and death.

Put to the test

Eight months after Cassidie Jackson was born, her parents, Latisha and Brandon, noticed their daughter’s lymph nodes felt like knots around her neck. They arrived at St. Jude, where doctors confirmed a diagnosis of ALL, which depletes the body’s number of infection-fighting white blood cells. Cassidie tolerated the first two rounds of chemotherapy, but her cell count plummeted after the third round of medications.

“Her belly, liver and spleen were all starting to swell,” Latisha says. “It was pretty mind-blowing.”

David Kalwinsky, MD, head of the St. Jude affiliate in Johnson City, Tennessee, ordered a genetic test that revealed Cassidie had inherited a defect for the enzyme thiopurine methyltransferase (TPMT). This defect prevented her from metabolizing the anti-cancer drug 6-mercaptopurine (6MP). As a result, Cassidie’s tiny body was amassing dangerously high levels of the toxic drug. Although the defect had not previously been seen in infants, St. Jude studies showed that TPMT-deficient patients could still benefit from 6MP if their doses were decreased. “She started taking only a quarter of the pill each time, and everything has been fine ever since,” Latisha says.

The TPMT mutations were discovered at St. Jude, as was the genetic test that is now routinely used by hospitals to screen children before 6MP is administered. The St. Jude discovery offers one example of how tailored treatments work when a single genetic variation interferes with drug response. While clearly of great importance, Evans calls this the “low-hanging fruit” of pharmacogenomics and says the science’s full potential won’t be realized until researchers discover more of the multiple gene variations that influence drug responses.

Hard work ahead

Completion of the Human Genome Project sparked dreams that medical breakthroughs would instantly materialize once scientists fashioned a map of the body’s 30,000 genes. The reality is that meaningful research takes time.

“We’re dealing with diseases that require at least 10 years of follow-up to see what goes on with patients in the long term,” Relling says. “There’s nothing you can do to speed up that process. St. Jude has the advantage with a head start of about 15 years in its pharmacogenomics research, and we’re just now getting back mature data. Some people are starting at point zero.”

In her roles on a Food and Drug Administration pharmacology committee and involvement in multi-institutional pharmacogenomics and treatment groups, Relling is urging fellow scientists to begin incorporating pharmacogenomic studies into their clinical research. She says the slow reaction to jump on the bandwagon is due in part to the difficulty in obtaining federal funding for what is perceived as a mundane aspect of research.

“There really isn’t anything sophisticated about keeping track of each medication you give a child and knowing exactly when they do and don’t get side effects, but you cannot do pharmacogenomic research without that,” Relling says. “It just takes hard work, time and money, but we feel that the payoff will be great.”

According to Evans, St. Jude has more extensive and detailed follow-up of children with cancer than any other hospital in the world.

Leading the way

The more glamorous side of pharmacogenomics has been the emergence of DNA microarray technology, which allows researchers to screen thousands of genes at once to reveal a person’s genetic fingerprint. Evans says that better diagnostic tools will be needed so that doctors will be able to translate microarray data into treatment plans.

“A doctor 20 years from now is not going to look at a DNA sequence output for an individual patient and be able to say, ‘Okay, this is how I pick the drug,’” says Evans, who likens the results of a genetic test to the barcodes on a can of tomato soup. “You can’t figure out what the soup costs by looking at it on the grocery store shelf; you have to take it up to the scanner to find out that it costs $1.79. So a genotype is like a bunch of barcodes, and the readout is going to tell you what that means.”

Developing tools that can read the hundreds of thousands of genetic variations could take time. Moreover, before pharmacogenomics can be clinically successful, legal assurances are needed so that genetic information cannot be used by insurance companies to discriminate against patients with high genetic risk for health problems.

“We’re still in the transition period with pharmacogenomics,” Evans says. “These are early days, and nobody yet fully knows what impact it will have.”

Pharmaceutical companies are among those unsure of what to make of tailored therapies, seeing little financial benefit from producing limited quantities of drugs that could help small segments—like children with leukemia—compared to blockbuster drugs that can be sold to the masses. Companies could have even less incentive to keep certain drugs on the market if genetic testing further shrinks populations into subsets.

“St. Jude pushes and makes sure drugs continue to be available for pediatric diseases, even when they aren’t necessarily commercial successes. There aren’t many other places that have the resources to do so,” Relling says.

Whatever the future is for pharmacogenomics, St. Jude will continue its quest to bring the benefits of individualized therapies to kids around the world. “We’re trying to bring the power of the human genome to kids with cancer and other catastrophic diseases,” Evans says. “We’re interested in taking this research and developing it into therapies for childhood cancer. That’s been our mission for 40 years.”

Reprinted from Promise magazine, autumn 2004

 

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