Potential new drug treats blood disorders by halting overproduction of blood cells

February 24, 2011

GAINESVILLE, Fla. — Like a switch stuck in the on position, the bone marrow can churn out blood cells that bloat internal organs and clog blood vessels, leading to life-threatening disease.

Now University of Florida scientists have discovered a potential new drug that can throw the switch on the runaway blood cell-production mechanism. The drug shrinks cell-gorged organs and stems the overproduction of blood cells, and the researchers are working toward bringing it into clinical trial in one year.

“The disease has a path it’s going to take and you need to be able to alter that path — our drug does that to a reasonable extent,” said Peter P. Sayeski, an associate professor of physiology and functional genomics in the UF College of Medicine, who led the research team.

The work, funded in part by the National Institutes of Health and the American Heart Association, is described in the current issue of the Journal of Biological Chemistry.

The new drug, dubbed “G6” by the researchers, targets a group of life-threatening and hard-to-diagnose diseases called myeloproliferative neoplasms, or MPNs, that occur when the bone marrow cranks out too many red cells, white cells or platelets because of a mutant form of a protein called Jak2 that is key to blood cell formation. The condition is estimated to affect about 170,000 people in the United States, according to data from the MPN Research Foundation, also known as the MPD Foundation.

“These bone marrow cells are replicating and growing out of control because one very important protein is stuck in the on position,” said Dr. Christopher R. Cogle, an associate professor of hematology/oncology in the UF College of Medicine and a member of the UF Shands Cancer Center.

The result is blood counts so high they elevate patients’ risk of stroke, bleeding, infection and blood clots in various parts of the body. Ironically, the condition can also lead to low blood cell count and anemia symptoms, because it impedes the flow of normal cells from the bone marrow into the blood stream.

Doctors typically treat patients for years with low-dose oral chemotherapy that keeps the disease in check, but doesn’t cure it. And long-term chemotherapy carries its own risk of secondary blood cancers and leukemia, and of depressing normal blood cell counts.

“There is a need for new drugs, because these diseases are progressive and terminate fatally, and there’s no single good treatment to date,” said Dr. Richard Silver, a professor of medicine and director of the Leukemia and Myleoproliferative Disease Center at New York Presbyterian-Weill Cornell Medical Center.

The UF researchers, along with colleagues at the University of South Florida, Heriot-Watt University in the United Kingdom, and Budapest University of Technology and Economics in Hungary, used computer technology to identify a chemical compound that can bind to the mutant protein and, in effect, turn it off. The compound belongs to a family called stilbenoids, which are known to slow cell growth and have antioxidant and tumor-suppressing properties.

In laboratory studies of cell cultures and in mice, the new drug reduced swelling in the spleen, corrected the unhealthily low ratio of white to red blood cells in the bone marrow and decreased the percentage of immature blood cells circulating through the body.

“This drug is a very promising and could significantly improve patients’ lives and possibly increase their survival,” Cogle said.

Other drugs that inhibit the action of the mutant protein are already in clinical trial, some with encouraging preliminary results, including shrinking the spleen in 40 percent of patients who take it. But they do not seem to change the blood cell composition within the bone marrow as the new drug does.

“What makes this interesting is that we altered the disease in the bone marrow,”said Sayeski, who is also a member of the UF Shands Cancer Center. “If you’re not treating the source then you can’t cure these patients.”

Still, much more work must be done before the needs of all patients with MPN are addressed, and before there is a solution that changes long-term prognosis for the disease, said Barbara Van Husen, president of the MPN Research Foundation.

The researchers, who are seeking funding necessary to translate their discovery into the clinic, are continuing to study precisely how the new compound works against disease and to determine optimal dosages and develop bulk production methods.

“The woods are lovely, dark and deep — there’s a long road you have to travel before you get a compound that works,” Silver said. “It’s interesting, but they’ve got a long way to go.”