UAMS study ‘promising’ in bone cancer treatment
BY NELL SMITH

Posted on Thursday, December 25, 2003

Researchers at the University of Arkansas for Medical Sciences believe they have identified the gene 
that triggers painful bone destruction in patients suffering from multiple myeloma. 

A research team led by John Shaughnessy Jr., director of the Lambert Laboratory of Myeloma Genetics at UAMS, 
reports in today’s issue of The New England Journal of Medicine that an overproduction of a molecule called DKK1 
may be responsible for bone fractures and weakness that characterize myeloma, a plasma cell cancer. 

Shaughnessy and his research team are now developing a drug to rid the blood of DKK1 and halt bone deterioration. 
"If we could stop this molecule," he said, "we could possibly shut down the whole process." 

The UAMS researchers are also studying the gene’s role in postmenopausal osteoporosis and in prostate cancer. 

The discovery of its function in multiple myeloma could impact the approximately 50,000 Americans suffering from the disease. 
At least 80 percent of multiple myeloma patients suffer from bone destruction, the leading cause of death for these patients. 
About 11,000 die every year from the disease. 

Multiple myeloma patients typically survive only a few years. The disease is nearly always fatal. 

Most myeloma research has concentrated on the cells that destroy bone, 
but Shaughnessy followed a hunch that the real problem was occurring with the cells that form bone. 

In healthy people, bone-destroying cells and bone-forming cells work together, 
balancing each other, to constantly regenerate new, strong bones. 

The UAMS researchers discovered that in myeloma patients, plasma cells — which are present in the bone marrow — secrete too much DKK1. 

An overload of this molecule, the researchers believe, essentially kills the cells that form bone. 
Without any cells to regrow bone, the bone-destroying cells are left to wear away bone. 
"What this does," Shaughnessy said of the gene, "is it triggers a whole cascade of events 
that lead to the loss of the boneforming cell and the hyperactivation of the bone-destroying cell, and then the patient is done." 

It’s a "promising" discovery, said Anne Quinn Young, program director for the Multiple Myeloma Research Foundation, 
a New Canaan, Conn.-based organization that raises money for myeloma research. 
"The gene that they’ve identified seems to interfere with the regrowth of new bone 
which obviously would perpetuate the lesions which cause a tremendous amount of pain 
and lead to a lot of fractures in a lot of myeloma patients as well," Quinn Young said. 

The Multiple Myeloma Research Foundation has funded UAMS myeloma research but did not finance this particular study. 

Shaughnessy said the next step is to develop a drug that absorbs the excess DKK1 to keep it from damaging the bone-forming cells. 

The potential therapy would stop further bone deterioration, but it’s unlikely to help revive damaged cells. 
"If we got early detection of myeloma, and then started giving this therapy what we could do is possibly prevent it from ever progressing." 

He said a therapy could begin clinical study within the next six months. 

Dr. Gerard Karsenty, professor of genetics at Baylor College of Medicine in Houston, 
said the UAMS findings are "potentially very significant.
" Still, he said, it’s premature to extend the findings to a drug therapy. 
"The challenge will be to devise a therapeutic tool that will affect only the osteoblasts, the cells making bone," 
he said, "and that is maybe a little bit more down the road." 

Linking the conclusions in this study to osteoporosis, a disease that results in brittle bones, is also premature, Karsenty said. 

But Shaughnessy said he plans to study the possibility that DKK1 may play an important role in osteoporosis. 
He believes that estrogen may regulate the DKK1 molecule, allowing for the possibility that DKK1 is linked to post-menopausal osteoporosis. 
"We’ve got this hypothesis that smoking actually exacerbates osteoporosis through the hyperactivation of this molecule," he said. 

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Link had some experimental treatment during the course of his myeloma so it's quite possible he contributed to this research.
-Jake
(12/25/03)