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Researchers identify promising gene target for neuroblastoma therapy

Thomas Look, senior author of the study

Dana-Farber scientists 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 its activity for their continued survival and 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 by the Friends for Life Foundation, founded by parents of a young DFCI patient to support neuroblastoma research.

The study appears in the Oct. 16 issue of Nature. "Our timing is good," says Thomas Look, MD, the study’s senior author, "because a new inhibitor of the ALK receptor is currently showing promise in clinical trials in adults, and should be available soon for clinical trials in children. 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."

Using high-powered gene-sequencing technologies, the researchers found five never-before-identified mutations in ALK in 8 percent of the neuroblastoma tumor samples studied. The mutations were in a portion of the gene responsible for the enzymatic activity of the ALK receptor, a structure 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 in the test cells.

"We are really happy about the success of this study, which was conducted by Rani George [MD, PhD] and Takaomi Sanda [MD, PhD] with a great deal of help from Matthew Meyerson [MD, PhD] and Nathaniel Gray [PhD] and their teams at Dana-Farber, and Gary Gilliland [MD, PhD] and Dr. Stefan Frohling of Brigham and Women’s Hospital," Look says.

Other co-authors of the study include Dana-Farber’s William Luther II, Yebin Ahn, Jianming Zhang, PhD, Wen-Jun Zhou, PhD, Lisa Diller, MD, Megan Hanna, and Heidi Greulich, PhD, of Dana-Farber.

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