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Flavopiridol and Rhabdoid Tumors

Posted on Monday, April 21, 2008

Plant Extract Targets Deadly Childhood Cancer

cancer cell attacked by immune system Flavopiridol—an extract of a medicinal plant from India—appears to offer real potential for hard-to-treat rhabdoid tumors. For the first time, researchers have shown that this experimental drug can halt the growth of rhabdoid cancer cells, both in a laboratory dish, and in mice.

Rhabdoid tumor is a very rare—and highly aggressive—cancer of the kidney, brain, central nervous system, and soft tissues that occurs in very young children. Because rhabdoid tumors are so hard to treat, only 15 percent of children with this cancer will survive two years. Chemotherapy and other conventional treatments aren’t very effective on rhabdoid tumors, for several reasons.

“One reason is that the current treatment regimen of rhabdoid tumors is not based on the biology of the tumor and is not based on the understanding of what is required for the survival of these tumors,” explains lead study author Ganjam V. Kalpana, PhD, professor in the Department of Molecular Genetics at Albert Einstein College of Medicine in New York. “Another possibility is that the unique genetics and pathobiology [disease process] of these tumors makes them naturally resistant to even the most aggressive chemotherapy regimen.”

Yet another reason rhabdoid tumors have been hard to treat is that until recently, doctors believed that they were just another form of a rare kidney cancer called Wilms’ tumor. Researchers now understand that rhabdoid tumors are a unique form of cancer, and they have a better understanding of how these tumors form.

Dr. Kalpana and her colleagues have discovered that the development and survival of rhabdoid tumors hinges on a protein called cyclin D1, which is involved in regulating the cell cycle. This protein, when left unchecked, enables the uncontrolled cell growth that causes cancerous tumors to form. In fact, researchers have found that cyclin D1 tends to be overproduced in certain types of tumors.

Based on their understanding of how rhabdoid tumors form, Dr. Kalpana and her colleagues have been trying to develop more targeted therapies for this cancer. They chose flavopiridol because it targets cyclin D1, the suppression of which has been found in earlier studies by Dr. Kalpana’s group to reduce the survival of rhabdoid tumors. They tested flavopiridol on rhabdoid tumor cells in the laboratory, and in mice implanted with rhabdoid tumors.

After five days of treatment, flavopiridol killed 95 to 100 percent of the rhabdoid cells. In the mice, treatment with 7.5 mg/kg of flavopiridol five days a week for two weeks significantly inhibited tumor growth compared to the control mice. Most of the tumors either partially or completely stopped growing, according to Dr. Kalpana.

How might flavopiridol work against rhabdoid tumors? The researchers believe that it stops the cancer cell cycle and triggers a process of natural cell death called apoptosis. The effects of flavopiridol on tumors correspond to a decrease in cyclin D1.

Despite flavopiridol’s promise, there are concerns about its potential toxicity. A few of the mice died during the study, although the researchers aren’t sure whether this was due to the drug or to the tumor. Previous studies have suggested that flavopiridol might be safe enough to use in children and could be administered in doses that are effective against rhabdoid tumors.

Dr. Kalpana plans to conduct human clinical trials of flavopiridol in the near future. Considering the lack of treatment options for rhabdoid tumors today, she is hopeful that her research will lead to more effective biological therapies for this serious childhood cancer.

Source:
Smith ME, Cimica V, Chinni S, Challagulla K, Mani S, Kalpana GV. Rhabdoid tumor growth is inhibited by flavopiridol. Clinical Cancer Research; 2008;14:523-532.

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