Improving the power of prediction

Gene expression adds molecular correlate to tumor-grading system for prostate cancer, holds promise for therapy targets
From left, Alan Huang, Ruth Dumpit, Ilsa Coleman, Roger Coleman and Drs. Daniel Lin, Elahe Mostaghel, Pete Nelson and Lawrence True collaborated on a study that pinpoints molecular features to help predict how prostate-cancer cells will behave. Their findings could help identify genes to target for therapy and point to possible biomarkers of aggressive prostate cancer. Photo by Stephanie Cartier

Prostate cancer — unlike many cancers — is a disease with which many men can live. The tumors tend to grow very slowly and are often better left untreated. But some prostate tumors behave badly, ignoring the normal cell growth-control mechanisms. Such cancer can aggressively spread and is often lethal. So the question becomes how to foresee which is which.

Hutchinson Center scientists, along with colleagues at the University of Washington and other universities, have pinpointed molecular features to help predict how prostate-cancer cells will behave. Their findings, published in the July Proceedings of the National Academy of Sciences, could help identify genes to target for therapy and point to possible biomarkers of aggressive prostate cancer.

The Gleason grade

The current method for predicting outcome looks at the cancer under a microscope and grades, or visually describes, the cells. Prostate cancer has a specific grading system called a Gleason grade.

While the Gleason grade is often accurate, there is a lot of gray, said Dr. Pete Nelson, an investigator in the Human Biology and Clinical Research Divisions and one of the study's authors. "Not every pathologist will assign the same grade to a cancer," he said. "It's a very subjective determination, and the ramifications are great."

Using an 86-gene model, the researchers were able to determine what genes were turned on in low- or high-grade prostate-cancer cells with 76 percent accuracy. The study represents the first systematic attempt to distinguish these molecular features to produce a more objective predictor of outcome.

MAOA inhibitors

Nelson said if certain proteins can be associated with a specific grade of cancer, there is potential to use those as targets for therapy. He and his colleagues are collaborating with Emory University researchers to develop antibodies for clinical diagnosis. "The issue with prostate cancer hasn't been diagnosing it, but diagnosing the ones that really need treatment," he said.

The scientists also found a significant association between more aggressive cancers and high levels of a protein called monoamine oxidase A (MAOA) in more than 800 prostate samples. MAOA-inhibiting drugs have been used to treat depression for many years. "These drugs are readily available, so we're doing some experiments now to see if inhibiting MAOA will affect the growth of cancer cells," Nelson said.

The National Institutes of Health and the Pacific Northwest Prostate Cancer Research SPORE (Specialized Program of Research Excellence) funded the three-year study. The SPORE initiative involves more than 50 investigators in Seattle and Vancouver, B.C. The National Cancer Institute awarded $12.7 million to the Center in 2002 to lead a multicenter, five-year investigation into the genetic mechanisms of prostate-cancer progression. Understanding how and why prostate cancer can turn deadly is key to developing therapies that may effectively treat men with recurrent or advanced prostate cancer, for which there is no cure. One of the SPORE's goals is to create a genetic blueprint to help understand the molecular biology of prostate cancer at all stages of its progression.

"We're one of the few places that could assemble this whole team," said Nelson, who is also an associate professor of medicine, pathology and genome sciences at UW. "This study is unique in its extensive collaboration between the University of Washington and the Hutchinson Center. Through the UW, we had access to the clinical samples and the pathology input, and the Center provided the technological side, biostatistics and bioinformatics. It truly is team science."

Prostate cancer is the most common male cancer in the United States; an estimated 1.5 million Americans live with the disease, which affects one in six and is the third-leading cause of death from cancer in men. An estimated 234,000 men will be diagnosed this year and about 27,350 will die of it, according to the American Cancer Society.

Study contributors

Contributors to the study include lead author Dr. Lawrence True, UW, along with Department of Urology colleagues Drs. Paul Lange, Robert Vessella and Daniel Lin; Drs. Alan Huang and Elahe Mostaghel and Ilsa Coleman, David Gifford and Roger Coleman of the Human Biology Division; Sarah Hawley and Dr. Beatrice Knudsen of the Public Health Sciences Division; Dr. Tomasz Beer, Oregon Health & Science University; Dr. Edward Gelmann, Lombardi Comprehensive Cancer Center, Georgetown University; Dr. Milton Datta, Emory University; and Dr. Leroy Hood, Institute for Systems Biology.

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