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Researchers identify promising gene target for neuroblastoma therapy
Date:10/15/2008

BOSTON--Researchers at Dana-Farber Cancer Institute have identified a set of previously unknown mutations in a single gene in 8 percent of neuroblastomas, tumors of the nervous system that occur in young children and account for approximately 15 percent of all childhood cancer deaths.

The discovery is intriguing because a small "targeted" molecule inhibitor caused neuroblastoma cell lines carrying two of the mutations to die when treated in the laboratory. This suggests that when mutations activate the gene, known as ALK, tumors become "addicted" to -- or dependent on -- the mutated gene for their continued growth. Therapies designed to inhibit ALK may offer an effective approach to the disease.

For the research team and Dana-Farber itself, the finding is especially rewarding because funding for the study was provided in part by the Friends for Life Foundation, founded by the parents of a young Dana-Farber patient to support neuroblastoma research.

The study appears in the Oct. 16 issue of the journal Nature. The lead author is Rani George, MD, PhD, and the senior author is A. Thomas Look, MD, both from Dana-Farber.

Using high-powered gene-sequencing technologies, Look and his colleagues found five never-before-identified mutations in ALK in 8 percent of the neuroblastoma tumor samples studied. The mutations were all in a portion of the gene responsible for the enzymatic activity of the ALK "receptor," which transmits growth and survival signals to the cell. Some of the mutations give neuroblastoma cells the ability to proliferate even without the molecules that normally activate the receptor in a highly controlled way, the researchers found.

To see whether such haywire growth can be stopped, investigators mixed a powerful ALK-blocking molecule into batches of test cells whose ALK receptors harbor each of the newly discovered mutations. The small molecule inhibitor, TAE684, halted proliferation and brought on the death of cells with the most common mutation, designated F1174L, as well as cells with another of the mutations.

When investigators treated human neuroblastoma cells harboring the F1174L mutation with TAE684, the responses were just as dramatic as they had been in the test cells. The results were confirmed when researchers used a second technique for shutting down ALK genes with the F1174L mutation.

"Our timing is good because there is a new inhibitor of the ALK receptor that is currently showing promise in clinical trials in adults, and which should be available soon for clinical trials in children," said Look. "We are very hopeful that this drug will have activity in children whose tumors have these mutations. More studies are needed, but we are excited by the possibility that this drug and others like it will represent a major step forward for some children with neuroblastoma."


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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert

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