image Now that scientists have made tremendous progress in deciphering the Human Genome—the roadmap that determines our genetic makeup—the real work of applying this information to human medicine has begun. Doctors have long known that people sometimes differ in their responses to medicines, including painkillers, antibiotics, antidepressants and drugs for allergy, asthma, seizure, heartburn, and AIDS. Now, pharmaceuticals companies are targeting these differences by tailoring drugs to subgroups of people with certain disease genes.

The idea is to cultivate very specific medications that will be effective in people with a certain gene while sparing use—including the potential side effects of use—in people without the gene. Researchers have coined a name for this new science: pharmacogenetics, or pharmacogenomics, the study of how genes affect the way people respond to medicines. The ultimate goal is to create so-called “designer drugs” matched to unique genetic profiles.

Cancer Therapies in the Lead

The genes of many cancers differ from noncancer genes in the same individual. These cancer genes are often very active, and this activity potentially provides scientists with new targets for effective cancer treatment. For example, in 1998, the Food and Drug Administration approved the cancer drug Herceptin for the treatment of metastatic breast cancer. Herceptin is effective only in people with breast tumors that contain an overactive HER-2 gene. Twenty-five to thirty percent of all breast cancer patients have tumors which possess this abnormal gene activity. If doctors can determine excessive HER-2 activity in a tumor, they can use Herceptin to block the effects of the HER-2 gene and improve cancer survival. While Herceptin can be lifesaving in some patients, it also has serious potential side effects which must be balanced against its benefits.

Likewise, the leukemia drug Gleevec is effective in only a minority of people with chronic myeloid leukemia whose cancers have a gene that makes an abnormal leukemia-causing protein, BCR-ABL. Studies are underway to see if the benefits of Gleevec might be seen in other tumors as well. It has been recently approved for the treatment of gastrointestinal stromal tumors, dermatofibrosarcoma protuberans (DFSP), and four, rare blood diseases:

  • Relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
  • Myelodysplastic/myeloproliferative diseases (MDS/MPD)
  • Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL)
  • Aggressive systemic mastocytosis (ASM)

Other highly-targeted cancer drugs include Avastin, Erbitux, Tarceva, and Rituxan. None of these treatments are by themselves effective cancer cures, but in selected patients, they may greatly increase the effectiveness of standard anticancer treatments.

Identifying Natural Variations

Even though we all have the same overall number of genes, what contributes to our individuality, including our susceptibility to disease and reactions to medicines, are the unique variations within our own set of genes. These are naturally occurring differences, known as single nucleotide polymorphisms, or SNPs. Among the more than three billion pairs of DNA building blocks in each person’s genome, only about 0.1% of them vary from person to person. Yet these three million genetic variations are at the heart of pharmacogenomics research.

By digging deeper into our molecular blueprints, medicine will become more tailored to groups or individuals with certain genetic flags. Scientists hope that understanding these genetic variations will increasingly explain individual differences in how drugs are absorbed and metabolized, their side effects, and their overall effectiveness. Some of this understanding has begun to find its way into clinical applications.

In early 2005, the FDA approved AmpliChip CYP450, a test that measures variations in two genes that play a role in the metabolism of some commonly prescribed drugs. The test’s manufacturer claims AmpliChip can reduce the chances of unwanted drug reactions if doctors use it to guide their prescriptions of drugs known to be metabolized through one of the two measured genes. Test results may also allow dosages to be adjusted for those persons whose genes lead them to metabolize drugs unusually rapidly or unusually slowly.

The AmpliChip test and similar new technologies may lead to an era of “personalized medicine." According to Felix W. Frueh, PhD, Associate Director for Genomics, Office of Clinical Pharmacology and Biopharmaceutics at the FDA’s Center for Drug Evaluation and Research, this can be characterized as giving “the right dose of the right drug for the right indication for the right patient at the right time.”

Earlier Diagnosis, Tailored Treatment

Advances in molecular analysis offer the promise of improvements not only in individualized treatment, but in early disease diagnosis as well. If researchers know the genes or gene products to look for, diseases may be found earlier, potentially even before symptoms are apparent or the disease process really gets going—an obvious advance in the case of monitoring for recurrent cancers, for example. In 2004, the Oncotype DX Breast Cancer Assay became available with the intention of better predicting the risk of breast cancer recurrence. It is a panel test designed to detect the presence of 21 cancer-related genes. Studies suggest that results of this test (performed on a biopsy sample of breast tissue) can help doctors decide which treatments are most likely to be effective for an individual—as well as predicting the risk of tumor recurrence.

Future Prospects

Personalized medicine offers several other as-yet unfulfilled promises:

  • Identifying people at risk for disease
  • Earlier intervention—Researchers hope that quicker treatment may translate into more effective treatment and better outcomes for patients.
  • Better drugs developed more quickly—As scientists understand the genetic variations and molecular pathways involved in a disease, pharmaceutical companies hope to develop highly targeted drugs more quickly than is the norm today.

Before personalized medicine can be widely applied, however, much more research is necessary to fully decipher the genetic biomarkers associated with disease and drug reactions. Many personalized medicine tests may require that patients submit DNA samples for evaluation, or provide doctors and laboratories with genetic information, which could severely threaten privacy if used in an unauthorized manner. Developing secure safeguards against unauthorized use of our genetic data may prove every bit as difficult as creating the laboratory tests on which the science of personalized medicine depends.