$15 million grant extends study of how genes affect cancer chemotherapy

July 13, 2005

The National Institute of General Medical Sciences and the National Cancer Institute have renewed funding for a research project based at the University of Chicago to investigate how a person's genes influence his or her response to anti-cancer drugs. The renewal will provide $3 million for the project in the first year and nearly $15 million over five years. It follows a previous award of $11 million for four years.

Understanding variation in the genes that control drug metabolism and toxicity will increase the benefits of cancer chemotherapy by enabling doctors to determine the best possible dose of a drug for each patient. Precise dosing should improve each patient's response to therapy and produce fewer side effects.

The project, known as the Pharmacogenetics of Anticancer Agents Research (PAAR) Group, teams investigators from the University of Chicago with colleagues at St. Jude Children's Research Hospital in Memphis; the University of Texas MD Anderson Cancer Center in Houston; and the University of Pittsburgh. The research team includes prominent specialists in genetics, drug metabolism, pharmacology, new drug development, cancer chemotherapy, statistics, medical ethics, and molecular diagnostics.

Mark Ratain, MD, the Leon O. Jacobson Professor of Medicine and chairman, committee on clinical pharmacology and pharmacogenomics at the University of Chicago will continue to serve as chairman of the group, assisted by vice-chair, pharmacologist Mary Relling, PharMD, of St. Jude.

"Precise dosing is extremely important for cancer chemotherapy because many of these drugs are most effective at the highest possible dose yet they are also quite toxic," said Ratain. "But finding the right dose is difficult because patients vary radically and unpredictably in how they respond to these drugs. Some patients can have life-threatening side effects at a dose that may have little toxicity for someone else the same size and weight."

"Our goal is to determine how an individual's genetic makeup controls the ways he or she responds to these drugs--how the medications are absorbed, distributed in the body, broken down, and eliminated--and to use that knowledge to determine the best possible dose for each patient."

The investigators have already demonstrated considerable success describing how genetic variations can alter the benefits and risks of these drugs and have a track record of working together successfully on related projects.

In 2003, for example, researchers from the University of Chicago showed how variations in a single gene contributed to side effects causes by a widely used anti-cancer drug known as irinotecan (Camptosar®). Ratain and PAAR colleagues found that cancer patients with two copies of a particular version of a gene called UGT1A1 often suffered from low white blood cell counts, which can lead to serious--and even life-threatening--infections, even at standard doses. Patients with a slightly different version of the same gene had almost no risk at the same dose. Patients with one copy of each version had intermediate risk.

The test for UGT1A1 variation has been available at the University of Chicago since 2003. On June 7, 2005, because of this study, the FDA required amendment of the package insert for Camptosar® to include a warning that patients with a particular UGT1A1 genotype should receive a lower starting dose.

"These results emphasize the need to identify patients genetically predisposed to severe side effects from certain drugs," said Ratain. "Susceptible patients could take lower doses of that drug, or switch to a different drug, while patients who aren't susceptible could be given higher, more effective doses."

The PAAR grant is part of a nationwide research effort, the Pharmacogenetics Research Network, a collaboration of scientists supported by the National Institutes of Health to study how an individual's genes affect the way he or she responds to medicines. The goal of this research is to help tailor drug prescriptions to match each person's unique genetic make-up.

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