Scientist Finds How Cancer Triggers Bone Disease, Eyes Treatment

By David Hammer Associated Press Writer

LITTLE ROCK, ARK. (AP) –– An Arkansas scientist has discovered that a human gene is used by at least one type of cancer to cause bone disease, and treatments could be developed to stifle the combination’s destructive powers.

Experts in the study of multiple myeloma, a form of bone marrow cancer that kills about 12,000 people in the United States each year, are hailing the work of John Shaughnessy, Jr, published in the New England Journal of Medicine.

Using the University of Arkansas for Medical Sciences’ collection of multiple myeloma samples, the largest such collection in the world, Mr Shaughnessy and his team found that the protein encoded by a gene called DKK1 is harnessed by myeloma cancer cells to destroy bone.

Working under the tutelage of renowned myeloma researcher Dr Bart Barlogie, Mr Shaughnessy was analyzing the 35,000 human genes in myeloma tumor samples a year and a half ago when he realized that DKK1 was the pivotal molecule in the bone disease that accompanies the cancer.

“Of the thousands of proteins we looked at, the inhibition of only one showed results,’’ he told The Associated Press. “So, it’s powerful. It results in a cascade of events that goes even beyond multiple myeloma.’’

Before Mr Shaughnessy’s team began its work, it was already known that DKK1 molecules could de-activate the cells that rebuild bone. Contrary to popular belief, bone marrow is living tissue that constantly strips away and rejuvenates cells.

But Mr Shaughnessy said his “eureka moment” came when he realized that myeloma tumor cells were turning DKK1’s normal function to their own destructive means.

He said the tumor cells make so much DKK1 that it overwhelms another protein that activates bone-forming cells, effectively paralyzing them and letting the tearing-down process go unchecked.

“The pit-forming cells keep going and there’s nothing to come in to fill in the potholes,” he said.

The Connecticut-based Multiple Myeloma Research Foundation passed on a chance to fund Mr Shaughnessy’s work two years ago, but heralded the announcement of the work as a cause for hope for the 45,000 Americans who are living with –– typically dying within three years –– the disease.

“The identification of any gene that is over- or underexpressed in myeloma cells is extremely promising,” said Anne Quinn Young, the foundation’s program director. “What will set it apart will be whether antibodies can be quickly identified and developed for treatment. There are several aberrant genes in myeloma, but few drugs identified to hit those targets.”

Mr Shaughnessy said he already is performing culture trials to develop antibodies that can whisk the DKK1 away from bones. Dr Barlogie, who is overseeing the work, said tests on live mice are next and could lead to drug approval in the next two years.

“John has envisioned ways to interfere with myeloma’s negative attack so the [bone-building cells] can function normally again,” Dr Barlogie said.

Because of DKK1’s “cascade of events,” Mr Shaughnessy thinks it may play a role in bone disease in other types of cancer, or even in noncancerous osteoporosis. His UAMS colleague, Dr Stavros Manologas, first suggested that DKK1 may be elevated in postmenopausal women with osteoporosis in the journal Science last year.

In addition, there is evidence that DKK1 is not only used by cancer cells, but also sends a signal that helps gird the malignancies against chemotherapy. Dr Barlogie hopes Mr Shaughnessy’s team will be able to find a way to intercept that signal and turn the tables, harnessing the DKK1 to kill the cancer.

“We have 300 patients already profiled; those will be analyzed and we’ll develop a model using stem-cell transplant therapies,” Mr Shaughnessy said. “We’re very hopeful.”