New Treatment for Childhood Neuroblastoma Targets ALK Gene Mutations

The mutations were located in the ALK gene, which encodes a receptor tyrosine kinase. Neuroblastoma, an embryonal tumor of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive and fairly insensitive to chemotherapy; relapse is common and almost uniformly fatal.

Investigators at the Dana-Farber Cancer Institute (Cambridge, MA, USA) employed high-powered gene-sequencing technologies to identify five mutations in the kinase domain of ALK, of which three were somatic and two were germ line. The mutations activated the ALK gene, allowing neuroblastoma cells to proliferate even without the usual molecular signals that normally modulate the receptor.
The investigators reported in the October 16, 2008, issue of the journal Nature that the low molecular weight drug TAE684 could inhibit the activity of the most common mutation, F1174L. The drug halted tumor proliferation and stimulated apoptosis.

"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 senior author Dr. A. Thomas Look, professor of pediatric oncology at the Dana-Farber Cancer Institute. "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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Dana-Farber Cancer Institute