June 12, 2002 MINNEAPOLIS / ST. PAUL -- A simple test can be used to identify patients with the most aggressive prostate cancers, even among patients whose tumors are at the same stage, according to research at the University of Minnesota.
The degree to which prostate cancers have progressed is determined by the Gleason grading system, which is based on the shape and microscopic appearance of tumors. Patients with higher grades of tumor are in more advanced stages of the disease, but the grade does not tell how aggressively the tumors have been growing or metastasizing. The new test was developed by cancer researcher Akhouri Sinha, a professor of genetics, cell biology, and development, faculty member of the University of Minnesota Cancer Center and research scientist at the Minneapolis Veterans Affairs Medical Center, and his colleagues. The work will be published in the June 15 issue of Cancer. Donald Gleason, who developed the Gleason grading system, is a co-author.
After skin cancer, prostate cancer is the most common form of cancer in U.S. men, according to National Cancer Institute statistics. More than a quarter of men diagnosed with cancer have prostate cancer. The disease strikes black men more often than white; Asian and American Indian men are affected less often. The Gleason grading system assigns tumors a score between two and 10, with 10 being the most advanced cancer. Patients with a Gleason score from seven to 10 have a higher risk of dying of prostate cancer than those with lower scores, but some patients with higher scores outlive some with lower scores.
"This means that within any score, there are biologically aggressive and less aggressive forms of cancer," said Sinha. "This makes it more difficult to predict outcomes for individual patients."
In order to invade surrounding tissue and escape to blood vessels, cancer cells produce high levels of an enzyme called cathepsin B (CB), which destroys proteins in the connective tissue that holds cells in place. But cells also produce natural inhibitors of CB called stefins. The researchers reasoned that prostate tumors in which levels of inhibitors were equal to or higher than CB would be less aggressive. But if CB was higher, the tumor would be more likely to spread.
Working with prostate surgery samples from 97 prostate cancer patients and eight patients with a benign enlargement of the prostate, the researchers measured the ratio of CB to the inhibitor stefin A in prostate tissue. They used tissue from Gleason grade 6 tumors, which appear relatively homogeneous under the microscope. They found that the ratio of CB to stefin A was significantly higher in patients whose cancer had spread to one or more pelvic lymph nodes than in patients whose nodes were clear.
"The ratio of CB to stefin A reveals differences in tumors that are not visible under the microscope," said Sinha. "If this test were done on tumors of newly diagnosed patients, we would have an indication of which cancers were most aggressive, and we could give those patients aggressive treatment. Those patients whose tumors show ratios of one, or less than one, may require less aggressive treatment. This approach could also be used for breast and colon cancer."
The work was supported by the U.S. Public Health Service and the Research Service of the Minneapolis Veterans Affairs Medical Center.
In previous work, Sinha devised a treatment for prostate cancer that zeroes in on prostate specific antigen, or PSA. High blood levels of PSA are a common first signal of prostate cancer. Prostate cells, including prostate cancer cells, display PSA on their outer surfaces. Working with mice, Sinha used a treatment that consisted of an antibody to PSA coupled to an anti-cancer drug. The antibody attached to PSA molecules on prostate cells, which prompted the cells to absorb the antibody-drug compound. In metabolizing the compound, the cells split off the drug, which killed the cells. The antibody-drug compound attached preferentially to PSA on prostate cells rather than to circulating PSA in the blood or to any other organ. Sinha said almost any chemotherapeutic agent could be coupled to the antibody. That work is ready to be tested in a phase 1 clinical trial, for which Sinha seeks funding.
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