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$11-million grant supports study of how genes affect cancer chemotherapy

University of Chicago Medical Center

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The National Institute of General Medical Sciences and the National Cancer Institute have awarded more than $11 million over four years to a team of researchers, based at the University of Chicago Medical Center, to investigate how a person's genes influence his or her response to anti-cancer drugs. Understanding variation in the genes that control drug metabolism and toxicity will improve dosing, increase the benefits of cancer chemotherapy and reduce side effects.

The Pharmacogenetics of Anticancer Agents Research (PAAR) Group includes investigators from the University of Chicago, St. Jude Children's Research Hospital in Memphis, the Tulane/VA Environmental Astrobiology Center in New Orleans, and the University of Pittsburgh. It is chaired by medical oncologist Mark Ratain, M.D., professor of medicine and chairman of the committee on clinical pharmacology at the University of Chicago. The vice-chair is molecular and clinical pharmacologist Mary Relling, Pharm.D., 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 the ways 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 PAAR Group will initially concentrate on a group of anticancer drugs known as topoisomerase inhibitors, powerful but toxic substances used in children and adults to treat a wide variety of cancers.

The investigators have already demonstrated considerable success in unravelling the ways that genetic variation can alter the efficacy and toxicity of these drugs and have a track record of working together successfully on related projects.

Ratain, for example, found that the topoisomerase-II inhibitor amonafide is processed in the body by an enzyme that also helps metabolize caffeine. This discovery allowed his team to develop a simple test, using a cup of coffee, to predetermine how patients would react to the drug and to calculate the best dose for each patient.

More recently he has focused on genetic variation in the enzymes that metabolize a powerful and widely used anticancer drug known as CPT-11, or Camptosaur, which has proved effective against colon and other solid tumors. Ratain and colleagues have devised a clinical trial to test whether other drugs can alter the metabolism of CPT-11, allowing higher doses with fewer side effects.

Relling is an experienced pharmacologist who has studied genetic variation in the enzymes that control metabolism of the topoisomerase-inhibitor etoposide. Although an effective drug in the treatment of a common form of childhood leukemia, etoposide can cause genetic damage leading a secondary and often fatal form of leukemia years after the initial treatment.

"We have already used genetic tests to identify that a small percentage of patients are at a higher risk for the secondary form of leukemia because of a mutation in one of the genes that metabolize the anticancer drugs they receive," said Relling. "We are working to use state-of-the-art technologies to identify other mutations that may predispose to these second cancers, so that we may eventually be able to tailor cancer therapy based on a patient's genetic make-up."

In addition to Ratain and Relling, the research team includes prominent specialists in genetics, drug metabolism, pharmacology, new drug development, cancer chemotherapy, statistics, medical ethics, and molecular diagnostics (with a core gene array facility at Tulane).

The group's early studies will be carried out in tissue samples, including large bank of blood cell lines maintained at the University of Chicago and a human liver bank at St. Jude.

The next step will involve pharmacologic and genetic studies including patients enrolled in clinical trials at the University of Chicago and at St. Jude. Eventually clinical trials of new methods or agents to improve dosing could move into multi-center clinical trials through Cancer and Leukemia Group B, headquartered at the University of Chicago, and the newly formed Children's Oncology Group.

The PAAR grant is part of a nationwide research effort sponsored by the National Institutes of Health to understand how a person's genetic make-up determines the way a medicine works in his or her body, as well as what side effects the person might be prone to developing. The trans-NIH effort is designed to forge an interactive research network of investigators who will store data in a shared information library accessible to the scientific community.

"The outcome of pharmacogenetics research has the potential to improve the health of all Americans, by making the medicines of today and tomorrow safer and more effective for everyone," said Dr. Rochelle Long, a pharmacologist at NIGMS who spearheaded the pharmacogenetics initiative.


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