Custom-fitting a Drug for a Child with Leukemia

Today, 85% of children who are diagnosed with acute lymphoblastic leukemia, the most common childhood cancer, are cured of the disease. Unfortunately, the drugs which have made this possible can also have severe side effects, occasionally resulting in death. Included among those drugs is the thiopurine agent, 6-mercaptopurine (6-MP).

Physicians have understood for a long time that children died because these drugs destroyed healthy bone marrow as well as cancer cells. But they could not explain why this happened to some children and not to others—until key discoveries made at the Mayo Clinic provided the necessary insight into the influence genes have on how an individual responds to a given drug. So began the era of "pharmacogenomic" medicine. The term reflects the profound influence that one's genetic make-up has on how therapeutic or toxic a drug may be.

The pathbreaking Mayo Clinic research into pharmacogenomics not only explained this phenomenon, it also led to the development of thiopurine prescriptions that are tailored to the genetic makeup of an individual child - a standard approach at Mayo since 1991. So important is this advance with thipurine drugs that a U.S. Food and Drug Administration panel recently approved it as the first drug in history to include pharmacogenomic instructions on its label.

While the full FDA had not acted on the recommendation as of October 2003, the principal investigator of the thiopurine reaction is greatly encouraged that the application of pharmacogenomics has reached this level. "It shows, I think, just how central our discovery was," says Richard Weinshilboum, M.D., an internationally renowned pharmacogenomics researcher with the Department of Molecular Pharmacology and Experimental Therapeutics. "Mayo truly was one of the founding centers in this field."

"The children who died as a result of drug toxicity often did so because they inherited genes that produced a faulty enzyme for metabolizing thiopurine drugs," says Dr. Weinshilboum. "It was absolutely tragic. This type of leukemia is the number one cancer in children. There are approximately 3,000 new cases in the United States each year."

The faulty enzyme, thiopurine methyltransferase, is known by the nickname TPMT. Dr. Weinshilboum's lab developed tests, including DNA tests that reveal the patient's genetically-determined ability to produce either efficient or faulty TPMT enzyme. That knowledge is then used to calculate the optimal dose of thiopurine drugs for the individual patient.

"The test now protects children who get two copies of the variant genes that impair the proper metabolizing of thiopurine drugs and can cause toxicity," says Dr. Weinshilboum. "These children require only about one tenth of the standard dose of 6-MP. It is rewarding to know that we can now not only cure 85 percent of children with this type of leukemia simply with pharmacologic therapy—no surgery, no radiation therapy—but we can also protect them from genetically-determined life-threatening thiopurine drug toxicity."

Mayo Clinic Positioned to Continue Pharmacogenomic Discoveries

Mayo Clinic is poised to play a leadership role in future pharmacogenomic advances for several reasons. In addition to its pioneering work in the field, its investigators currently pursue cutting-edge applications to other areas, such as determining individual doses of drugs used in psychiatry and breast cancer treatments. Moreover, Mayo Clinic's enduring commitment to translating basic research to patient-care assures that the discoveries of Dr. Weinshilboum's lab will continue to make a difference where it matters: in patients lives.

Mayo Clinic's long experience has been both deeply productive and highly influential. Dr. Weinshilboum chairs the Pharmacogenetics Research Network, a National-Institutes-of-Health-funded project that includes scientists from Mayo Clinic, Harvard University, University of California, San Francisco, Stanford University and the University of Chicago and many other academic medical centers. Network scientists provide expertise in specialized areas within the pharmacogenomics field and contribute to the development of a pharmacogenomics knowledge base to help disseminate understanding of how genetic variation among individuals contributes to differences in response to drugs.

Pharmacogenomics is the science of discovering the genetic basis for individual variations in drug response. It is also the science of using these genetic insights to individualize therapy for a variety of diseases and conditions.

Prior to the completion of the federally-funded Human Genome Project in 2001, the field was usually referred to as "pharmacogenetics"—a word coined in the 1950s. The term "pharmacogenomics" reflects the new knowledge base created by the Human Genome Project. The project deciphered the gene sequences of the genome - the entire human genetic complement that contains an estimated 35,000 genes.

Says Dr. Weinshilboum: "To the same extent that some of us are tall and others short, some of us are bald and others are not, there is also genetic variation in drug response. Those of us in the field of pharmacogenomics try to identify, understand, and use these genetic differences to improve patient care."

The Future of Pharmacogenomics

Pharmacogenomics represents a radical advance in medical history. In the past, most drugs were designed to work on the population level rather than being targeted for the individual patient. By reversing that trend, pharmacogenomics helps to refine the focus of treatment and makes drugs more effective and less toxic.

Rather than relying on the outward manifestation of disease—the signs and symptoms that physicians call the phenotype—pharmacogenomic medicine examines and treats the genotype. Think of the genotype as the inward manifestation of disease—the DNA itself is addressed first and matched with the way the disease presents in the patient—the phenotypic presentation.

In one approach, researchers use computers to gain access to the sequence of genes that encode proteins that might influence drug response. They then use DNA samples obtained from a National Institutes of Health's repository. They then sequence these genes, looking for common genetic variation.

"We find genetic variations in every gene we look at," says Dr. Weinshilboum. "From this, we can determine which of the common variations is functionally important, and immediately test it in a clinical setting."

Armed with pharmacogenomic insights, Mayo Clinic researchers collaborate with physicians who treat patients to give them the "inside scoop" about the genetic involvement in their response to drug therapy. This allows Mayo researchers to take their findings out of the lab and improve patients' lives more quickly. Researchers in Dr. Weinshilboum's group are working with Mayo physicians to team pharmocogenomic approaches with improved patient care in areas as diverse as breast cancer and psychiatric disorders.

Applying Pharmacogenomics to Psychiatry

One example of how pharmacogenomic research can be successfully applied to a disease specialty stems from collaboration between researchers and psychiatrists at Mayo Clinic. Psychiatrists now use a DNA test to screen for the best metabolic fit for certain drugs. And they are working on developing ways to use genotyping for accurate diagnosis. "Dr. Weinshilboum and his group are the experts here. We're very lucky to benefit from their expertise through our collaboration," says David Mrazek, M.D. chair of the Department of Psychiatry and Psychology.

A New Test—a More Effective Treatment for Depression

Just as children respond differently to the same anti-cancer drug, so do people respond differently to anti-depressants and alcohol. Within the same family, a slightly different genetic make-up can mean the difference between being able to enjoy a glass of wine and becoming alcoholic. It also can explain why one patient's life is radically improved through the use of a commonly prescribed anti-depressant such as Prozac, and another's remains muddled.

Dr. Mrazek applied pharmacogenomics to his field when he became interested in developing a test that predicts which anti-depressant best suits a particular patient. As the director of the Genomic Expression and Neuropsychiatric Evaluation Unit, he collaborated with the Department of Laboratory Medicine and Pathology to develop the new test.

Called p450 microarray analysis, the new test can reveal whether a patient has one or more genes that interfere with the body's metabolism of commonly prescribed antidepressant drugs.

"There is one enzyme that metabolizes about 50 drugs," says Dr. Mrazek. "This is an emerging field but being able to apply what we've already learned about genetic variation already allows me to take better care of the patient, and that's very exciting."

Genotyping helps physicians prescribe the most appropriate drug for their patients. It does this by revealing a patient's enzymatic activity level—whether it stimulates normal, slow, or rapid metabolizing of the drug.

"Drug companies produce a one-size-fits-all dose based on how the average person metabolizes a drug," Dr. Mrazek says. "That means if you have enzymes that make you metabolize slowly, you're vulnerable to side effects. And if you metabolize too quickly, the drug doesn't have enough time to have the intended effect. "

A New Era for Psychiatry: Accurate Diagnosis

In the near future, Dr. Mrazek hopes to use pharmacogenomics as a tool so that psychiatrists can make consistently accurate diagnoses. When it does, it will mark the beginning of a new era in psychiatry, one informed by the biological understanding of mental and emotional disorders. Accurate diagnosis is essential for treatment to be effective.

"Currently, psychiatrists rely solely on the phenotype for diagnosis," says Dr. Mrazek. "But relying solely on signs and symptoms sometimes leads to the wrong diagnosis or misses the fact that the patient may have an additional disease."

Dr. Mrazak is encouraged that Mayo Clinic pharmacogenomic studies now underway will result in a new tool that will make psychiatric diagnoses accurate. Psychiatrists know that symptoms reflect the way a person feels, and that the way a person feels is a product of their brain chemistry. Many drugs currently available seek to change that internal brain chemistry by manipulating the levels of important neurotransmitters. Serotonin in one such neurotransmitter.

"We are studying the genotype to identify defective transporters or receptor molecules that are not correctly processing serotonin," says Dr. Mrazek. "Once we can use genotyping to accurately diagnose the patient's disease, the next step will be to design drugs to stimulate the particular receptor and correct the problem."

Researchers are using microarray technology to investigate associations between subtypes of depression and problematic genes. They are conducting simple blood tests on multiple generations of families with similar illnesses. The study will increase understanding of the role of genomic variation in psychiatric illnesses such as depression, bipolar disorder, and schizophrenia. Alcohol addiction may be one of the diseases that can benefit from this approach.

"It would be a great help to have genetic evidence to show a person why their sister can drink sensibly but they must exercise particular care," says Dr. Mrazek. "With this information, we can target vulnerable populations for early treatment and preventive intervention programs in many types of psychiatric illnesses."

Pharmocogenomic Medicine

Mayo Clinic researchers say the pharmacogenomic approach to improved treatment will become increasingly common. Dr. Weinshilboum believes that collaborations such as Dr. Mrazek's work in psychiatry are typical of the Mayo Clinic research-patient care continuum that is central to the success of pharmacogenomic medicine.

In addition to his collaboration with Dr. Mrazek, Dr. Weinshilboum collaborates with researchers in breast cancer as well. One such project examines the influence of genetic variations in a woman's response to tamoxifen, a drug often prescribed to prevent recurrence of breast cancer. Because the study is ongoing, results are not yet available.

But as interest in—and evidence for—pharacogenomic medicine grows, Dr. Weinshilboum fully expects to see more collaborations that scrutinize both the therapeutic and the toxic response to a given drug.

"Modern biological and medical science today is an international collaborative activity," Dr. Weinshilboum notes. "Many of our collaborations have been with investigators conducting leukemia trials in Sheffield, United Kingdom, and in Copenhagen, Denmark. In addition, we rely on extensive collaborations with investigators across the United States and, of course, here at Mayo. At Mayo Clinic we excel at collaboration—and we have the enormous clinical and research capacity to continue making significant contributions to this exciting field."