$10 million grant enables research on gene-guided chemotherapy

Aug. 29, 2005 -- Taking into account that each of us has unique physical characteristics partly determined by variations in our genes, pharmacogenetics researchers at Washington University School of Medicine in St. Louis are finding ways to personalize cancer treatments.

Their research program has now received a $10 million, five-year grant from the National Institutes of Health (NIH) to continue their innovative approach that began in 2001. At that time, a group of researchers at the University, led by Howard McLeod, Pharm.D., director of the Siteman Cancer Center Pharmacology Core, established a program that is part of the Pharmacogenetics Research Network, a nationwide collaboration of scientists supported by the NIH.

Pharmacogenetics seeks to make use of genetic information to guide medicinal therapies, and McLeod is a recognized leader in the field. McLeod's program, called CREATE (Comprehensive Research on Expressed Alleles in Therapeutic Evaluation) (web site: http://pgen.wustl.edu), aims at using genetic information to predict how well anticancer therapies will work in different cancer patients.

"Pharmacogenetics has shown a great deal of promise for cancer treatment," says McLeod, professor of internal medicine, of genetics and of molecular biology and pharmacology. "Funding a center like ours at this high level is the NIH's way of trying to turn this promise into reality."

One step toward this reality was achieved recently when the Food and Drug Administration approved a genetic test to help guide the use of a standard cancer-treatment drug called Camptosar™. The work of McLeod and others identified a variation of a gene, UGT1A1, involved in the breakdown of Camptosar. The variant of UGT1A1 increases the toxicity of the drug, and patients with a copy of the variant are at risk of severe, even fatal toxic reactions to Camptosar. Physicians can now test for the genetic variant to help decide how best to treat cancer patients.

Importantly, Camptosar's effect in the body is mediated by several genes in addition to UGT1A1. For example, one gene produces an enzyme that converts the drug to a form 1,000 times more active. Other genes make enzymes that can oxidize and deactivate the drug. Still others are involved in Camptosar's transport into cells, where its ultimate target lies. Therefore, a combination of genetic markers may be the best strategy for determining individual response to the drug.

For this reason, McLeod and his colleagues are investigating networks of genes that regulate how chemotherapeutic agents function in the body as they seek genetic variations that lead to medically relevant outcomes. As their studies progress, information gathered about multiple related genes goes to build representations of the webs of cellular components that control the way the drug works and is processed in the body.

This research provides a much more thorough understanding of individual reaction to chemotherapy and will allow physicians to optimize drug selection and drug dosing for each patient according to variations in pertinent genes. The research may also help identify new targets in tumor cells and in that way guide development of new chemotherapeutic agents. In addition, the approach can lead to information about how genes affect the toxicity of chemotherapeutic agents.

"Oncologists have seen that in some patients a certain drug will produce good tumor shrinkage with no side effects," McLeod says. "But they also see patients who have severe side effects with the same drug whose tumors continue growing. In individual patients, pharmacogenetics approaches can compare the profile of tumor genes with that of normal tissues with an eye toward maximizing killing of tumor cells and minimizing toxic effects in normal tissue."

Colon cancer has served as a model disease for the research group, but the principles they are uncovering have also been applied to prostate cancer, non-small-cell lung cancer, breast cancer and ovarian cancer.

"The concepts we are building are likely to lead to a situation where the anatomy of cancer becomes less important," McLeod says. "So we won't necessarily think about breast or colon or lung cancer. We'll think about the genetic foundation of each cancer and the resulting biological characteristics and choose an appropriate treatment."

The goal of the CREATE program—translation of genetic discoveries to clinical interventions—makes it an important facet of the University's BioMed 21 initiative, which is dedicated to using the latest knowledge of the human genetic blueprint to develop new ways to diagnose, treat and ultimately prevent a variety of common human diseases.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare. Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 200-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.