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News Archive - Progress Newsletter Fall 2002 Online

Research Roundup

 

U-M scientists find new genetic marker for prostate cancer

Using the power of advanced DNA microarray technology, scientists at the U-M Medical Shcool have identified a gene that triggers production of a specific protein in cancer prostate cells. Because the protein is present in large amounts only in malignant cells and is easily visible when stained, it could improve the accuracy and sensitivity of screening tests for prostate cancer -- the second leading cause of cancer-related deaths in men.

The protein is an enzyme involved in fat metabolism called a-methylacyl-CoA racemase, or AMACR for short. AMACR has never before been associated with any type of cancer, according to Mark A. Rubin, M.D., and Arul M. Chinnaiyan, M.D., Ph.D., the scientists who directed the U-M research study. Results were published in the April 3 issue of the Journal of the American Medical Association.

"We detected high levels of AMACR protein in over 95 percent of more than 300 prostate tissue samples that contained localized cancer," says Dr. Chinnaiyan, an assistant professor of pathology in the U-M Medical School. "Equally important, we found very little or no AMACR protein in benign prostate tissue or in tissue with non-malignant cell changes. We then evaluated the clinical utility of AMACR immunostaining on 94 prostate needle biopsies; the sensitivity and selectivity ratings were 97 percent and 100 percent."

"AMACR is one of approximately 20 genes which we found to be over-expressed consistently in prostate cancer," Dr. Chinnaiyan adds. "This doesn't mean that these genes cause prostate cancer, but they can be a marker or indicator of prostate cancer for diagnostic or prognostic purposes."

Improvement over PSA tests

AMACR's accuracy and specificity is a major improvement over the Prostate Specific Antigen (PSA) test-the only diagnostic screening test currently available to physicians. "The beauty of AMACR is that it is cancer-specific and concentrated only in malignant cells," says Dr. Rubin, an associate professor of pathology and surgery in the U-M Medical School. "PSA can't differentiate between cell changes caused by cancer and those caused by benign changes in the prostate. As a result, PSA tests have a high rate of false positives, which can mean repeat needle biopsies and unnecessary surgery."

U-M researchers say AMACR could act as a diagnostic marker for other types of cancer too. When Drs. Rubin and Chinnaiyan surveyed cells from different types of cancer looking for AMACR over-expression, they found it in colorectal, prostate, ovarian, breast, bladder, lung, renal cell, lymphoma and melanoma-with the highest amounts present in colorectal and prostate cancer.

Research on the genetic and molecular profile of prostate cancer using DNA microarray analysis is part of a major initiative under way at the U-M Comprehensive Cancer Center. Its goal is to link molecular genetics with clinical outcome for all types of cancer.

"By looking at gene expression, we can learn so much more about a tumor," says Cancer Center Director Max Wicha, M.D., U-M distinguished professor of oncology, and a professor of internal medicine. "It explains why one patient's tumor remains localized, while another tumor spreads. It will allow us to tailor specific therapies to the gene expression profile of each patient."

"Previous prostate cancer studies focused on one gene at a time," Dr. Chinnaiyan says."With DNA microarray technology, we can 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."

The complete news release is on-line.

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U-M study finds new target in war against graft-versus-host disease (GVHD)

University of Michigan scientists have recently discovered how graft-versus-host-disease, a common and deadly complication of life-saving bone marrow transplants, attacks and often kills its victims.

At least 500 Americans die from GVHD every year. this discovery could help prevent these deaths and reduce the risk of hospitalization and debilitating side effects for more than 5,000 Americans who receive donor bone marrow transplants annually, primarily to treat leukemia and other cancers.

Results from the U-M study, published in the June 2002 issue of Nature Medicine, show how skin, liver and gastrointestinal cells in mice with GVHD are destroyed from a distance by a fire-storm of immune system proteins called inflammatory cytokines. Human clinical trials, based on findings from the Nature Medicine study, are now underway at the U-M Comprehensive Cancer Center.

Understanding the role of cytokines in GVHD
"Cytokines turn healthy immune cells in donated bone marrow -- something given to cure patients -- into lethal weapons capable of killing them," says James L. M. Ferrara, M.D., Director of the U-M Blood and Marrow Transplant Program and a profesor of internal medicine and pediatrics in the U-M Medical School.

Dr. Ferrara says the study calls into question a widely accepted assumption that T cells-immune cells that attach to and kill just one target cell at a time-are the major cell-killing agents of graft-versus-host disease. "It's the difference between a direct attack by ground troops and a general air strike," Dr. Ferrara explains.

The study's findings will help scientists focus GVHD prevention strategies on its primary killing agents-especially two powerful cytokines called tumor necrosis factor-alpha and interleukin-1. "Now that we know cytokines are the major cause of GVHD-induced cell damage, we can look for ways to neutralize them or block their production," Dr. Ferrara says.

The risk of GVHD is highest following a bone marrow transplant from an allogeneic donor-someone other than the patient or the patient's identical twin. Symptoms of acute GVHD usually begin three to six weeks after the transplant, often after the patient has been discharged and appears to be recovering well.

Instead of the patient's body rejecting a donated organ, as occurs in an organ transplant, the donated bone marrow, called the graft, rejects cells in the host or patient. GVHD's primary targets are skin, liver and epithelial cells lining the stomach and intestines of the host. Damaged by heavy doses of radiation and chemotherapy used to destroy the patient's cancerous bone marrow before the transplant, these cells secrete substances that activate antigen-presenting cells that are in the patient's immune system.

"Until now, researchers assumed that pre-transplant radiation killed all the host's antigen-presenting cells (APC's), so scientists discounted the importance of these cells in GVHD," says Takanori Teshima, M.D., Ph.D., a former U-M research scientist now at Japan's Okayama University. "But we found that a few APCs remain deep inside tissue. If even one percent survive, it is enough to trigger the graft-versus-host reaction."

When immune cells from the donor's bone marrow meet APCs carrying substances from host cells, some of the donor cells are sensitized to see the patient's cells as the "enemy." These cells respond by firing salvos of inflammatory cytokines, especially tumor necrosis factor-alpha and interleukin-1. The cytokine barrage transforms "good" immune cells in the patient's new bone marrow into an army of destructive effector cells all primed to attack and kill the host.

"Cytokines can travel through the bloodstream and, therefore, inflict their damage from a distance," Dr. Ferrara adds. "So there's no need for direct contact between donor effector cells and host target cells, and antigen expression on the host's epithelial cells is not required for development of graft-versus-host disease."

In his study, Dr. Teshima used strains of genetically altered laboratory mice, which expressed specific classes of antigens on APCs derived from donor bone marrow, but not on host target cells. "The availability of these chimeric mice allowed us to test most donor-recipient combinations involving major antigens called MHC molecules," he says. "Neutralizing TNF-alpha and interleukin-1 suppressed dramatically the mortality and morbidity of GVHD in mice."

Developing methods to block cytokines
Drs. Teshima and Ferrara believe blocking cytokines could preserve the ability of donor T cells to bind to and kill the patient's leukemia cells without risking the toxic effects of GVHD. "Since 90 percent of bone marrow transplants are given to patients with leukemia, it is important not to interfere with the direct-contact killing mechanism," Dr. Ferrara says.

In clinical trials under way at the U-M Cancer Center, Dr. Ferrara and colleagues are investigating new drugs that bind to and neutralize tumor necrosis factor. U-M physicians are testing these drugs to determine if they can prevent cell damage in patients with GVHD and lung disease after a bone marrow transplant. In a future study, Dr. Ferrara hopes to determine whether other drugs can block the original interaction between host APCs and donor immune cells, preventing the initial activation phase of acute GVHD.

For information on bone marrow transplant clinical trials, call the Cancer AnswerLine™ at (800) 865-1125.

The complete news release is on-line.

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