Genomics and Personalized Medicine : What Is Pharmacogenomics?

by Food and Drug Administration (FDA)

Genes determine the color of our eyes and shape of our bodies. Genes also determine our susceptibility to disease and how we respond to medicine.

Researchers believe that each person has about 35,000 genes. The complete set of genes together is known as the human genome, commonly referred to as "the instruction manual" for how the body works. Each gene carries instructions for making proteins, which direct the body's cells and functions.

Most cells have 46 chromosomes — 23 from each parent. Chromosomes contain thousands of genes, which are made up of deoxyribonucleic acid (DNA), the chemical material that is inherited.

Genomics is the study of an individual's gene structure, including how the genes interact with each other and with the environment. Experts say genomics has the potential to revolutionize the practice of medicine. That revolution, called "personalized medicine," includes the use of genomic information to improve the diagnosis of disease, as well as the prevention and treatment of disease.

An example of a preventive approach is when a genetic test predicts which diseases an individual is likely to develop. For instance, people who have certain mutations in the BRCA1 gene have a high risk of developing breast, ovarian, and possibly prostate, and colon cancers, according to the National Cancer Institute (NCI). Alterations in the BRCA2 gene have been associated with breast, pancreatic, gallbladder, and stomach cancers. An example of a treatment approach is when a genetic test determines whether a person is among the 10 percent of those for whom a particular drug is likely to work.

Felix Frueh, Ph.D., associate director for genomics in the Food and Drug Administration's Office of Clinical Pharmacology and Biopharmaceutics, says, "Personalized medicine tries to answer questions like: Why do some people get cancer and others don't? Why is cancer more aggressive in this person compared to that one? Why does this drug work for you and not me? Why does someone need twice the standard dose to be effective? And why do others need only half of the standard dose?"

"The goal of personalized medicine is to get the best medical outcomes by choosing treatments that work well with a person's genomic profile, or with certain characteristics in the person's blood proteins or cell surface proteins," Frueh says. Genetic information isn't usually meant to be used alone to make treatment decisions, but rather is used with other factors such as the patient's family history, medical history, clinical exam, and other non-genomic diagnostic tests.

What Is Pharmacogenomics?

The combination of drugs (pharmacology) with genomics is known as pharmacogenomics, the science that allows researchers to predict the probability of a drug response based on a person's genetic makeup. "It's about getting the right dose of the right drug to the right patient at the right time," Frueh says.

The science of pharmacogenomics has advanced significantly in the last five years, but it's still in its infancy and is mostly used on a research basis, says Larry Lesko, Ph.D., director of the FDA's Office of Clinical Pharmacology and Biopharmaceutics. "There are three main ways that pharmacogenomics is applied," Lesko says. "The first is to help predict the appropriate dose of a drug. The second is to target therapy to a subset of a disease. This means picking the most effective drug for the disease subset. And the third is to test viral genomics, such as in selecting treatment for HIV based on resistance."

The usual doses of drugs work well for most people. They are sometimes based on weight, age, and kidney function. But for someone who metabolizes a drug quickly, the typical dose may be ineffective and a higher dose may be needed. By contrast, someone who is a slow metabolizer may need a lower dose; the typical dose could cause toxic levels of the drug to build up in the blood.

When we take medicine, it moves through our body, gets broken down by drug-metabolizing enzymes, and interacts with countless proteins. "Genes regulate drug metabolism," Frueh says. "Differences in the sequence of a gene can cause differences in enzyme activity, which is a result of enzymes appearing in various forms in individuals. This is why different people process the same drug differently."

Mary Relling, Pharm.D., chairwoman of pharmaceutical sciences at St. Jude Children's Research Hospital in Memphis, Tenn., says that for children with leukemia, getting the dose wrong can mean the difference between life and death. "We want to keep harsher treatments away from children whose bodies can't tolerate them or don't need them," Relling says.

For example, St. Jude's routinely conducts a genetic test for defects in the enzyme thiopurine methyltransferase (TMPT). The defect prevents patients from metabolizing the anti-cancer drug 6-mercaptopurine (6MP). One patient may need a full dose; another, who has a mutation in the gene, may need less than 10 percent of that dose.

"Before this test, some patients needed blood transfusions or had to be hospitalized for infections, and we didn't know why," Relling says. "Now we can avoid some of the toxicity of the drug by testing all the children who come in and making dose adjustments based on their genetic test and response to therapy."

Targeted therapy, the second major aspect of pharmacogenomics, is also referred to as "tumor genomics," Lesko says. Tumors have different genomic variations, and genomic tests are helping doctors to identify cancers that are likely to respond to a particular treatment. Lesko cites the drugs Gleevec (Imatinib) for chronic myeloid leukemia, Tarceva (erlotinib) for lung cancer, and Herceptin (trastuzumab) for breast cancer as examples of targeted therapy.

Both Gleevec and Tarceva interact with enzymes called tyrosine kinase inhibitors. Turning off these enzymes prevents the growth of cancer cells. Herceptin targets tumors that produce excess amounts of the HER2 protein, which is produced by the HER2 gene. Overexpression of the HER2 protein causes a higher rate of cell growth. Before Herceptin is used, tumors must be tested to evaluate the amount of HER2 protein.

The third aspect of pharmacogenomics includes testing for drug resistance, Lesko says. For example, the HIV virus genome is always changing, and resistance testing can help doctors choose the drug that will best match the virus and suppress it. The TRUGENE HIV-1 Genotyping Kit is cleared by the FDA to detect genetic variations that make the HIV virus resistant to some anti-retroviral drugs. If drug resistance is discovered, a doctor can decide to try another treatment option.

About the Author

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