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Cancer prescriptions are written in genetic code.

The waiting was the hardest part for researcher Howard L. McLeod, PharmD. As a specialist in pharmacogenetics, the study of interactions between drug treatments and an individual’s genetic code, McLeod could see a day coming when doctors would use their patients’ genes to steer them away from potentially hazardous reactions to medications and toward beneficial outcomes.

But that day didn’t seem to be getting any closer. “It seemed like the best estimate was always that it would be another 10 years before we could put these kinds of approaches to use,” says McLeod. “Those 10 years just never seemed to end.”

About two years ago, McLeod decided he’d had enough waiting. With colleagues in several departments at the School of Medicine and Barnes-Jewish Hospital, he put together the first study in the United States that uses patients’ genetic information to modify their treatments.

Now about halfway finished, the study focuses on colorectal cancer patients and a gene that appears to be linked to how positively patients respond to chemotherapy and radiation treatments. Patients with a form of the gene that decreases their chances of having a good response are given added chemotherapy.

“Until now, clinicians treated everyone the same way and then scientists looked back and said, ‘Hey, by the way, this patient A, with this particular set of genes, has a better response to the treatment; or patient B, with these genes, has more toxicity,’” says Benjamin R. Tan, MD, a medical oncologist and assistant professor of medicine who is involved in the study. “In this unique project, though, we’re actually acting on that data prospectively to see if we can individualize treatment.”

To generate leads for genes that might potentially interact with a drug, scientists first assemble a list of the proteins known to interact with a drug. Pharmacogeneticists then check if changes in the genes for those proteins seem to correlate with changed treatment outcomes. “The good side is that it’s a very educated guess, and the bad side is that it’s still a guess,” McLeod says. “But it’s still much better than searching all 35,000 genes in the human genome.”

With support from the National Cancer Institute, McLeod’s research group recently conducted a review of several genetic markers tentatively linked to effects on colorectal cancer treatment. “Results from our studies of colorectal cancer will help us think about how we can begin to apply pharmacogenetics to other tumor types including lung, breast and prostate cancers,” he says.

McLeod notes that more than one gene is known to contribute to colorectal cancer, so a thorough pharmacogenetic approach to managing treatment will inevitably have to consider the potential effects on treatment of several different genes. And in the end, genetics is unlikely to account for all variability in patient responses to treatment. McLeod estimates that as much as 50 percent of that variability may stem from other factors, such as a patient’s diet.

Understanding these contributors to variability becomes a priority as more options for treatment become available. For 40 years, physicians had only one approved chemotherapy drug for colorectal cancers, but in recent years four new drugs have been introduced.

“Now that we have five drugs, how do we decide what to do? We have to find out information from our patients and their DNA to determine which drug will be most likely to give them the best results,” McLeod says.

“Pharmacogenetics lets us individualize this treatment, which is a prelude to surgery,” says Robert S. Malyapa, MD, PhD, assistant professor of radiation oncology. “We hope that this will have a positive effect on both tumor control and long-term survival.”

When patients agree to participate, a clinical trial coordinator takes a blood sample for DNA analysis. Scientists look at a gene in the patient’s DNA that can affect how much the patient’s cells make of a protein, thymidylate synthase (TS), that is the primary target for a major chemotherapy drug, 5-fluorouracil.

“This is pure translational research — really, what everyone is striving to do more of now,” comments David W. Dietz, MD, a colorectal surgeon involved in the study and an assistant professor of surgery. “It’s taking the latest basic science results and directly applying them to the care of patients.”

The pharmacogenetics trial includes many of the key elements that BioMed 21 seeks to encourage in research: it brings the latest in basic research to bear on patient care, it makes use of the new wealth of human genetic data now available, and it involves collaboration across several departments.

“This is really an example of multidisciplinary medicine at its best,” McLeod says. “We could never do this study if the radiation oncologists, medical oncologists, surgeons, radiologists and pathologists weren’t all 100 percent on board.”

McLeod anticipates that the study will finish early next spring. He’s not making any promises on how far that first step will take pharmacogenetics researchers, but he’s extremely glad to have finally set that step in motion.

By Jim Dryden