$10 million grant extends study of how genes affect cancer therapies

September 9, 2010

The National Institutes of Health have awarded $10.3 million to the University of Chicago's Pharmacogenetics of Anticancer Agents Research Group (PAAR) to investigate how a person's genes influence his or her response to anticancer drugs.

PAAR, continuously funded by the NIH since 2000, is part of the Pharmacogenomics Research Network (PGRN), a nationwide collaborative of scientists focused on understanding how genes affect a person's response to medicines in order to tailor drug prescriptions to match each person's unique genetic make-up.

Led by Mark J. Ratain, Nancy J. Cox and M. Eileen Dolan, PAAR Group researchers will study the genes that control drug metabolism and toxicity. Understanding the influence of variations in these genes 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 response to therapy and produce fewer side effects.

"Thanks to breakthroughs in genome sequencing technologies and our growing understanding of genetic variation among individuals, there has never been a better time to propel the field of pharmacogenomics,'' said NIH Director Francis S. Collins, MD, PhD. "Through these studies, we are moving closer to the goal of using genetic information to help prescribe the safest, most effective medicine for each patient."

The PAAR Group includes prominent specialists in genetics, drug metabolism, pharmacology, new drug development, cancer chemotherapy, statistics, medical ethics, and molecular diagnostics.

"Many of these drugs are most effective at the highest possible dose yet they are also quite toxic, so precise dosing is extremely important for cancer chemotherapy," said Ratain, the Leon O. Jacobson Professor of Medicine and director of the Center for Personalized Therapeutics at the University of Chicago.

"But finding the right dose is difficult. 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," he said.

The investigators have already discovered how genetic variations can alter the benefits and risks of several anticancer drugs. In 2003, for example, the University of Chicago team showed how variations in a single gene contributed to side effects caused by a widely used anticancer drug known as irinotecan and developed a genetic test to predict side effects. Because of this study, the FDA approved an amendment of the package insert for irinotecan 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."

"This is a very exciting network with top-notch scientists studying pharmacogenomics as it applies to different medicines and diseases" said Dolan, Professor of Medicine and Chair of Committee on Clinical Pharmacology and Pharmacogenomics. "We are able to leverage off of each other's expertise and learn about the latest approaches in the genomics field."

The National Institutes of Health plans to spend $161.3 million over the next five years to expand the Pharmacogenomics Research Network. The awards announced today include 14 scientific research projects and seven network resources, designed to assist the research groups by providing additional DNA sequencing capacity, statistical analysis expertise, standardized terminology for pharmacogenomics research, ways to learn about pharmacogenomics from de-identified medical records in health care systems, and expanding a 2-year-old international collaboration with the Center for Genomic Medicine at the RIKEN Institute in Yokohama, Japan.

The PGRN is funded by nine NIH components: the National Institute of General Medical Science; the National Heart, Lung, and Blood Institute; the National Cancer Institute; the National Institute on Drug Abuse; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Human Genome Research Institute; the National Institute of Mental Health; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and the Office of Research on Women's Health in the Office of the Director.

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