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UM research aims to improve tribal health
Every day, breast cancer patients across the world receive the chemotherapy drug tamoxifen. For most, this is a successful cancer-fighting drug, but not for all. One key to its effectiveness lies in each patient’s individual genes.
Erica Woodahl, assistant professor in the Department of Biomedical and Pharmaceutical Sciences at UM, specializes in an emerging field called pharmacogenomics (or pharmacogenetics) -- the study of how our DNA affects the drugs we take. Hired in 2007, she adds a new dimension to the department’s accomplished faculty.
“Right now, drugs often are prescribed in a one-size-fits-all fashion, but individual responses to medications can vary widely,” Woodahl says. “Pharmacogenomics looks at ways we can tailor drugs for individuals based on their genetic makeup.”
UM researcher Erica Woodahl
This summer, Woodahl will launch a five-year study to find out if pharmacogenetic testing can lead to more effective cancer treatments in American Indian populations. Specifically, she and her team will examine individual genotypes that affect response to tamoxifen. Her collaborators are Associate Professors Elizabeth Putnam and Mark Pershouse (with Woodahl in UM’s Skaggs School of Pharmacy) and the Montana Cancer Institute Foundation. Dr. Patrick Beatty at Missoula’s St. Patrick Hospital is the lead oncologist.
The $1.4 million slated for UM is part of a $10.2 million grant from the National Institutes of Health Pharmacogenomics Research Network (spearheaded by the National Institute of General Medical Sciences). UM joins the University of Washington, University of Alaska-Fairbanks, the Southcentral Foundation in Anchorage, Group Health Cooperative in Seattle and Puget Sound Blood Bank as partners in the grant, which is titled “Pharmacogenetics in Rural and Underserved Populations.”
While the grant starts in July, Woodahl’s preliminary work began upon her arrival in Montana from the Fred Hutchinson Cancer Research Center in Seattle, where she completed her postdoctoral fellowship.
“For more than three years, we have had a close dialogue with the Confederated Salish and Kootenai Tribes,” she says. “They were interested in research that could help tribal members with cancer.”
With the tribal council’s official approval of the study, Woodahl and her colleagues have the permission to enroll Salish and Kootenai participants. They have collected blood samples from volunteers recruited at powwows, health centers and other tribal gathering points.
Preliminary gene sequencing of samples from Salish and Kootenai tribal members indicates tamoxifen would not be an effective cancer-fighting drug for about 10 percent of the population. That percentage represents a significant risk, Woodahl stresses.
What is it about a person’s genes that would make tamoxifen a success or failure in stopping breast cancer reoccurrence? To succeed, tamoxifen must be activated by a drug-metabolizing enzyme in the liver. That enzyme produces a metabolite of tamoxifen called endoxifen, which is the key compound that binds to estrogen receptors on cancer tumor cells. Denied of estrogen, those cells cannot proliferate.
However, some people with certain genotypes in this drug-metabolizing enzyme do not effectively convert tamoxifen into the active endoxifen. These patients will have less success with tamoxifen as a breast cancer treatment.
The team next will take a close look at the pharmacogenomics in breast cancer patients from the Salish and Kootenai tribes being treated with tamoxifen. They will identify whether patients have genotypes for efficient or deficient drug metabolism and then compare tamoxifen and endoxifen levels.
“This study offers direct benefits to the participating cancer patients,” Woodahl says, “and it may yield important results in drug therapy for American Indian populations.”
Two other research projects build on Woodahl’s earlier pharmacogenomics work in Seattle. She and her graduate students focus on a protein called P-glycoprotein. The name may not be familiar to most of us, yet this protein plays a hefty role in the human body as a drug transporter that pumps compounds — including drugs and toxins – out of cells and tissues throughout the body.
Woodahl’s lab examines how changes in the three-dimensional structure of P-glycoprotein (caused by genetic variation) can affect its ability to function. When medications fail or cause toxic side effects, doctors turn to the scientists to find out why. P-glycoprotein is important for mediating drug levels of many classes of drugs, including those for cancer, HIV, epilepsy and others. Woodahl believes her research can contribute to improved drug treatment in these areas.
In a related project, Woodahl studies P-glycoprotein from an environmental angle, investigating how exposure to pesticides can lead to diseases that result from toxins entering the brain.
“P-glycoprotein protects the brain from toxic substances circulating around in our blood,” she says. “But changes in the function of the protein may allow toxins to accumulate in the brain, and these people could be more susceptible to neurodegenerative disease, such as Parkinson’s.”
Woodahl wants to find out if genetic variation in P-glycoprotein lessens the ability of this crucial drug transporter to keep pesticides, such as Paraquat, from entering the brain. Paraquat is one of the most widely used herbicides in the world.
A career focusing on more effective cancer treatments and toxicity issues in the environment was not something Woodahl stumbled upon in college courses. One pivotal event during middle school in her hometown of Missoula shaped her career choice.
In 1992 Taxol gained approval as a groundbreaking cancer drug, initiating a rush to harvest the Pacific Yew tree that harbored the wondrous natural compound. Why, Woodahl wondered, couldn’t scientists figure out how to replicate that cancer-fighting drug in a lab? (Researchers have since developed synthetic forms of Taxol). Suddenly, chemistry and biology classes became more meaningful.
Woodahl graduated from Missoula’s Hellgate High School in 1994 and earned an undergraduate biochemistry degree from the University of Notre Dame in 1998, followed by a Ph.D. in pharmaceutics in 2004 from the University of Washington, where she discovered pharmacogenomics and never looked back. She appreciates the cross-disciplinary opportunities among the UM faculty with specialties in neuroscience, environmental toxicology, cardiovascular pharmacology and medicinal chemistry.
“What we all hope to see is that translation of medicine from the lab bench to the bedside, so we will be able to better treat, control and prevent diseases,” Woodahl says.
— By Deborah Richie Oberbillig
|(Above) UM's Erica Woodahl removes some DNA samples from a minus-80-degree-Celsius freezer in her lab.