Decoding prostate cancer

Chemotherapy gets personal for cancer patients

Like most killers, prostate cancer leaves fingerprints. Every malignant cell has a unique pattern of active genes and proteins that spells the difference between benign, localized or metastatic tumors.

Normal prostate tissue (above) has n organized structure with prostate epithelial cells (stained blue) which surround and line prostate glands (white areas). Photo credit: Mark Rubin, University of Michigan Medical School

Hidden in this molecular profile are answers to questions doctors hear every day: Is surgery really necessary? Can I afford to wait? Will the cancer come back?

Until now, physicians have been unable to decode these fingerprints, which hold the key to understanding the relationship between gene expression and future prognosis for men with prostate cancer. But a new U-M study published in Nature offers scientists their first look at the genetic and molecular profile of prostate cancer.

"Our study has important applications in the diagnosis, prognosis and treatment of prostate cancer," says Mark Rubin, M.D., a co-author of the Nature paper and an associate professor of pathology and urology. "

The ultimate goal is to help physicians determine which patients need immediate, aggressive treatment and which can be watched and treated conservatively."

Cancerous tissue is completely isorganized. The uncontrolled growth of malignant cells has destroyed the normal glandular structure. Photo credit: Mark Rubin, University of Michigan Medical School

Researchers used more than 80 complementary DNA micro-arrays to assess gene expression profiles in four types of tissue. These included normal prostate tissue from men with and without prostate cancer, tissue with benign changes, localized prostate cancer and aggressive, metastatic cancer.

"Previous prostate cancer studies focused on one gene at a time," says Arul Chinnaiyan, M.D., Ph.D., an assistant professor of pathology, who directed the study. "Using microarray technology, we were able to look at thousands of genes in prostate cells simultaneously. This is important, because it is most likely that many genes are involved in the development and progression of prostate cancer - each controlling a different step in the process."

While some of the genes identified in the U-M study are well known to cancer researchers, many others have never before been associated with prostate cancer. Two of these new genes are hepsin and pim-1, which could turn out to be important new clinical biomarkers for prostate cancer, according to Dr. Rubin.

"It has been 15 years since the Prostate Specific Antigen (PSA) test became available in 1987," says Dr. Rubin. "This approach could give us many new diagnostic tests within three to five years. Eventually, it could lead to a diagnostic kit physicians could use to determine the best treatment and prognosis for their patients with prostate cancer."

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Chemotherapy has long been known to be an effective way to control the spread of cancer. But its benefits don't come without the price of possible devastating side effects including hair loss and fatigue. Sometimes without warning, even more serious side effects can happen that result in illness and hospitalization. Now, a new study may have found a way to eliminate the unpredictability of chemotherapy without jeopardizing the treatment.

Physicians at the U-M Cancer Center are conducting a study on chemotherapy doses for breast cancer patients. This population, according to Anne Schott, M.D., medical oncologist and assistant professor of hematology/oncology, often has chemotherapy prescribed to them as a form of treatment.

"For a woman who has just been diagnosed with breast cancer, her treatment options include chemotherapy, as well as surgery, hormonal therapy and radiation treatments," she says. "But to control the cancer from spreading, usually most cases require chemotherapy."

Problems with chemotherapy

Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. The body, usually the liver or the kidneys, breaks down the medi-cation. The amount of chemo-therapy given is most often based on a patient's height and weight. But this method does not always lead to the best dose for patients. Dr. Schott explains, "The problem with this approach is that it doesn't take into account individuals' metabolism of chemotherapy, which could vary greatly depending on what medicines they are on and the functioning of their heart, liver or kidneys."

Researchers at the Cancer Center are trying to fix the problem by tailoring doses with results from the Erythromycin Breath Test, a test - originally developed at the U-M - that can determine how a patient's body breaks down the antibiotic erythromycin. Erythromycin is metabolized in the same way as many chemo-therapy drugs, by the enzyme CYP3A4.

"We're using the Erythromycin Breath Test to tell us how fast an individual will metabolize other drugs that use the same enzyme," she says. "In the study we're conducting, we're looking at the breast cancer drug Taxotere, which uses that same enzyme, to tell us how to dose the chemotherapy drug."

The Erythromycin Breath Test works like this: The patient gets an injection of a very small and safe amount of radioactive erythromycin. After they get the injection, they wait 20 minutes for the drug to be metabolized and then they blow air out into a bag. From there, doctors can measure traces of carbon dioxide in their breath. Carbon dioxide is one of the chemicals produced when erythromycin is broken down by the body.

"By using the breath test, we can actually pick a dose of Taxotere that's specific for the individual, not just based on their height and weight," Dr. Schott notes. "By picking a dose that's specific for the individual, we will not have the risk of either overdosing or underdosing the individual."

Some study participants have already reported a positive effect. Gretchen Davenport was diagnosed with breast cancer in 1998.When it came back a year later, she enrolled in the Cancer Center study. "In my first run of chemo-therapy almost four years ago, I was very tired and had to have Neupogen," Ms. Davenport says. "But the cancer came back and I had to have chemotherapy again, so I came here to the Cancer Center. This time I had very few side effects. I wasn't tired and never lost my appetite."

Preliminary results show that tailored dosing allows doctors to achieve more consistent drug levels in the body, compared to just giving everyone the standard dose. Consistent drug levels are critical in fighting cancer cells. "We think it's very important to make sure we're still seeing the same effectiveness of the drug in the tailored dosing as we would if we gave the standard dose," Dr. Schott notes.

"Once this study is completed, we will expand to include drugs which have the same kind of metabolism," she says.

Gretchen Davenport hopes all women suffering with breast cancer can some day take advantage of tailored chemotherapy dosing. "I think it's wonderful what they can do," she says. "It makes you feel a lot better about getting chemotherapy, that you're getting a dose that's specifically for you."

"The ultimate goal is to help physicians determine which patients need imme-diate, aggressive treatment and which can be watched and treated conservatively."

For more information on the tailored dosing study contact the Cancer AnswerLine at 1-800-865-1125; or contact them via their web page.

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