DEC. 26, 2003 | Scientists at the University of Arkansas for Medical Sciences (UAMS) have discovered the mechanism that destroys bone in the deadly cancer multiple myeloma and are developing a drug to stop or reverse the process.

John Shaughnessy, Jr., Ph.D., and his research team in the Myeloma Institute for Research and Therapy at UAMS report in the New England Journal of Medicine today that they have identified a gene, called DKK1, which causes bone lesions in multiple myeloma, leading to debilitating and intractable bone pain and a higher risk of bone fractures, spinal cord compression, and life-threatening levels of calcium in the blood.

Shaughnessy is developing a drug that will act like a sponge in the bloodstream to absorb DKK1, potentially arresting and reversing the bone destruction that is the primary effect of multiple myeloma. Almost always fatal, multiple myeloma strikes about 15,000 people in the United States each year.

“We can do it. We have the strategy. The soluble receptor should stop DKK1 from binding to bone cells,” Shaughnessy said. The potential UAMS treatments include soluble receptor therapy or monoclonal antibody therapy. Pharmaceutical companies have developed similar approaches to treat leukemias and breast cancer.

Shaughnessy’s team in the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Arkansas Cancer Research Center (ACRC) found that DKK1 inactivates osteoblasts, the naturally occurring cells that cause bone growth, altering the natural balance of action between osteoblasts and bone-destroying cells called osteoclasts. “The paralysis of the bone-forming cells and the hyperactivation of osteoclasts result in a net loss of bone in patients with myeloma,” Shaughnessy said.

The UAMS research group is one of the first to use gene expression profiling to discover how a disease process works. Other researchers have shown that mutations in the receptor for DKK1 cause two inherited bone syndromes, but the UAMS team is the first to trace elevated levels of DKK1 to multiple myeloma.  Shaughnessy’s team also is exploring whether DKK1 is elevated in women with postmenopausal osteoporosis – a possibility that another UAMS scientist, Stavros Manologas, M.D., Ph.D., first suggested in the journal Science last year – or in other cancers that cause bone loss.

Shaughnessy is an associate professor of medicine in the UAMS College of Medicine. Myeloma Institute Director Bart Barlogie, M.D., Ph.D., and researchers Yupo Ma, Ronald Walker, Fenghuang Zhan, and Erming Tian, all of UAMS, and Erik Rasmussem of Cancer Research and Biostatistics in Seattle collaborated on the study that led to identification of DKK1. Shaughnessy and Barlogie have received research funding from the National Cancer Institute, part of the National Institutes of Health, and the Fund to Cure Myeloma and the Penninsula Community Foundation.

Shaughnessy linked DKK1 to bone disease using microarray technology, which measures the activity of all 35,000 human genes in each tumor sample in an experiment. In a related project, Shaughnessy is comparing variation in gene expression with variation in response to different drug treatments in patients with myeloma, using a technique he described in the journal Blood earlier this year. Now completing a larger, more definitive study of the technique, Shaughnessy anticipates establishing a method for “personalizing” treatment of multiple myeloma on the basis of individual patients’ gene profiles in 2004. 

UAMS has the largest myeloma treatment and research centers in the world. Led by Barlogie, the Myeloma Institute, located in the ACRC at UAMS, has achieved a median survival rate of six to seven years, even though the national median survival rate is roughly 2.5 to three years. Anti-DKK1 therapy may complement or even replace the current standard therapy, called autologous transplantation, which is to remove hematopoietic stem cells from the patient’s bone marrow, treat the patient with high doses of chemotherapy, and then replace the stem cells.

Links on This Page

UAMS Reports: http://www.uams.edu/today/2003/013003/myeloma_treatment.htm
New Gift: http://www.uams.edu/today/2002/121802/newgift.htm
Pharmaceutical: http://www.uams.edu/today/2002/120602/barlogiecelgene.htm
Myeloma Institute: http://myeloma.uams.edu/
Arkansas Cancer Research Center: http://www.acrc.uams.edu/
 
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