For bone marrow transplant patients, new class of drugs could improve safety, reduce side effects

Recent U-M study highlights improved screening procedure for breast cancer

U-M to head national study of targeted therapy for prostate cancer

For bone marrow transplant patients, new class of drugs could improve safety, reduce side effects

A new class of anti-cancer drugs, currently being tested in human clinical trials, reduces the severity of graft-versus-host disease or GVHD – a common and often deadly complication of life-saving bone marrow transplants – without suppressing the immune response required to kill lingering cancer cells.

Scientists at the U-M Comprehensive Cancer Center are the first to study the effect of these drugs, called HDAC inhibitors, in laboratory mice. Results of the U-M study were published in the March 4, 2004 online issue of the Proceedings of the National Academy of Sciences.

Healthy cells lining the small intestine of normal mice (left) compared with dead and damaged intestinal cells from mice with graft-versus-host disease (right).

U-M scientists have found that low doses of HDAC inhibitors have a powerful anti-inflammatory effect. This prevents the production of proteins called inflammatory cytokines, which cause the extensive cell damage seen in GVHD patients.

“What’s so exciting is that HDAC inhibitors already have been tested as a chemotherapeutic agent in people,” says co-author James L.M. Ferrara, M.D., director of the U-M’s Blood and Marrow Transplant Program and a professor of internal medicine and pediatrics in the U-M Medical School. “They have relatively little toxicity and the doses required to generate an anti-inflammatory effect are 50- to 100-fold lower than doses needed to kill cancer cells."

If HDAC inhibitors work as well in cancer patients as they did in mice in the U-M study, they could reduce the risk of death, hospitalization and serious side effects associated with bone marrow transplants used to treat leukemia and other related cancers. More than 5,000 Americans receive allogeneic bone marrow transplants annually. An allogeneic donor is someone other than the patient or the patient’s identical twin. Between 500 to 1,000 Americans die from graft-versus-host disease each year.

“An allogeneic bone marrow transplant is a double-edged sword,” says Pavan Reddy, M.D., an assistant professor of internal medicine in the U-M Medical School and corresponding author of the paper. “The good side is the graft-versus-leukemia (GVL) effect, which means that T cells from donated bone marrow, called the graft, will attack and kill any remaining cancer cells. GVL is the most potent known form of immune therapy against malignant diseases. Without GVL, the cancer will most likely return.

“The bad side is GVHD. In GVHD, T cells from donated bone marrow, in concert with inflammatory cytokines, attack the patient’s skin, liver and gastrointestinal tract,” Reddy explains. “The key is to block the inflammatory cytokines but leave the cancer-killing donor T cells untouched, since they are vital for an effective GVL response.”

In previous research published in the June 2002 issue of Nature Medicine, Ferrara and Reddy, with colleagues from the U-M Cancer Center, discovered that inflammatory cytokines are the major cause of GVHD-induced cell damage. Since then, they have been searching for ways to neutralize cytokines or block their production. Their current work with HDAC inhibitors is an extension of this earlier research.

In this current research, mice with cancer first received bone marrow transplants, and a subset were then treated with an HDAC inhibitor. The results were significant: The drug improved survival rates in post-transplant mice by 60 percent. Although some treated mice still developed GVHD, they had milder symptoms and less intestinal damage than mice that did not receive the drug. Moreover, in related studies Reddy confirmed that treatment with HDACs did not interfere with the beneficial GFL effect.

“We believe that this class of drugs may increase the expression of tumor suppressor genes or genes that trigger suicide in cancer cells, while inhibiting expression of genes that produce inflammatory cytokines,” Reddy says. “But clearly more research will be needed to know exactly how they work.”

“We are very excited about what this kind of therapy could mean to patients with blood- and marrow-related cancers who need a transplant, but have a high risk of developing graft-versus-host disease,” Ferrara says. “Only about 25 percent of BMT patients have a perfectly-matched sibling donor, so this is good news for the other 75 percent.”

For more information on cancer treatment and clinical trials at the U-M Comprehensive Cancer Center, call the Cancer AnswerLine at 1-800-865-1125 or visit their web site.

For more information on the U-M Cancer Center’s Blood and Marrow Program, visit their web site.

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Recent U-M study highlights improved screening procedure for breast cancer

Short of preventing cancer before it strikes, the next most critical objective is finding it as early as possible, with optimal precision. The annual meeting of the Radiological Society of North America in December 2003 provided a forum for U-M investigators from the Department of Radiology’s CAD Research Laboratory to report on new computerized systems they are developing to provide a “second pair of eyes” for doctors reading mammograms and other breast scans. In various stages of readiness for clinical use, these computer-aided diagnosis, or CAD systems use computers to improve the accuracy of interpretation of digital mammograms and breast ultrasound images.

These systems show great promise not only for better detection, but for distinguishing cancer from benign problems without a biopsy, and for tracking changes in a woman’s breast over time. Initial studies proved that a CAD system improved the ability of a highly experienced radiologist to differentiate between cancerous tumors and benign growths on ultrasound breast scans. Ultrasounds are often used after identifying a suspicious finding on a screening mammogram to help determine whether a biopsy is needed.

The team hopes the use of CAD systems will eventually spare women some of the “worried waiting” and additional imaging that can follow an abnormal mammogram, and minimize the number of confirming biopsies required. Ultimately, the goal of the lab is to develop a digital technology that combines the very different images from ultrasound and mammography to give a complete view of a breast mass.

The team developing these technologies exemplifies U-M’s multi-disciplinary approach. Led by Heang-Ping Chan, Ph.D., the CAD Research Lab group works closely with clinicians in the U-M Breast Imaging Division, led by Mark Helvie, M.D. The effort to combine ultrasound and mammography technology is being led by Paul Carson, Ph.D., director of the Basic Radiological Sciences division, in partnership with researchers from General Electric.

Notes associate research professor Berkman Sahiner, Ph.D., no one thinks computers will replace doctors anytime soon. “A radiologist looks at the patient’s entire case,” says Sahiner, “not just her breast images. But if radiologists work with computers, they could improve their accuracy and spare some women unnecessary biopsies.”

To read more about these or other current research findings at the U-M Comprehensive Cancer Center, visit News Releases.

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U-M to head national study of targeted therapy for prostate cancer

For patients with advanced prostate cancer, hormone therapy and chemotherapy are the established treatment options. But new “targeted” molecular therapies show great promise, not necessarily to replace chemotherapy, but to work with it for a better result.
That promise has led the National Cancer Institute (NCI) to place added emphasis on developing targeted therapies. Unlike chemotherapy, which kills cancer cells by causing direct damage, targeted therapies seek to block or interfere with key pathways that keep cancer cells surviving and growing. Urologic Oncologist Maha Hussain, M.D., contrasts them as “the difference between a shotgun and a smart-bomb. Targeted therapies are intended to succeed with minimal collateral damage.”

Hussain is the principal investigator on two new national trials studying the biological agent EMD121974 (Cilengitide). It is intended to shut down a cancer cell’s ability to mobilize and spread, while also impeding the growth of new blood vessels nourishing the cell. Preliminary studies at U-M confirmed that the agent attacks specific prostate cancer targets. As a result, the NCI has designated Michigan the lead institution for two trials which will soon begin recruiting patients.

The first involves 100 patients with metastatic hormone-refractory prostate cancer. Over a six-month period, two dose levels will be tested. Preliminary trials have confirmed the safety of the agent, and indicate it is tolerated with side effects less severe than comparable chemotherapy, even at a high dose.

A second trial with the same agent will study patients who have been treated with hormone therapy and have no visible cancer spread, but whose PSA levels are increasing. “For these patients,” says Hussain, “there is no known treatment. The cancer can’t be seen, but PSA levels tell us it is there. We want to know whether a targeted agent might delay the occurrence of visible disease in these patients.”

The treatment itself is novel, and so is the way it will be evaluated. A new technology will be employed along with scans and PSA scores, studying the presence of circulating prostate cancer cells. In cancer, most cells congregate in tumor form, but a small number of cells have also been shown to circulate in the bloodstream. A new technology pioneered at U-M attaches tiny iron pellets to the circulating cancer cells in a blood sample, then uses a magnet to separate those cells for precise study. Researchers can evaluate how many cells are circulating before and after the treatment (there should be fewer if the treatment is successful at preventing the spread of cancer), and can also look for the presence of the agent (Cilengitide) on the cells to determine whether it is attacking its intended target.

For more information on this and other clinical trials for advanced metastatic disease,visit the Urologic section of our clinical trials page, or call the Cancer AnswerLine at 1-800-865-1125.

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