A mutation in the anaplastic lymphoma kinase (ALK) gene can cause a rare inherited form of the childhood nerve cancer neuroblastoma, according to a new study.
Abnormal ALK also seems to play a significant role in the more common form of the disease, paving the way for new screening methods and treatments, report researchers in an article in the August 24 edition of Nature.
This work is very important, says Meredith Irwin, a research scientist at the Hospital for Sick Children in Toronto who was not associated with the study.
“Maybe it’s going to help us come up with a better treatment for patients with neuroblastoma,” Irwin says. “There are opportunities for therapies not just for neuroblastoma, but other cancer as well.”
Neuroblastoma is a particularly deadly cancer of the neuroendocrine system. Normally affecting those under the age of 5, 500 to 600 new cases—about 7 percent of childhood cancers—are reported each year in the United States. But with a mortality rate of up to 70 percent, neuroblastoma accounts for 15 percent of all childhood cancer deaths.
DNA analyses showed that eight of ten large, multigenerational families with a history of neuroblastoma possessed mutations that increased ALK activity, says study leader Yael Mossé, an assistant professor of pediatrics at the Children’s Hospital of Philadelphia. About 1 to 2 percent of neuroblastoma cases are of the familial or inherited type.
The researchers also tested nearly 200 tumor samples from the more common, or sporadic, type of neuroblastoma and found that 12 percent showed similar ALK mutations.
Adding short interfering RNAs to block the production of ALK caused significant growth reductions in all neuroblastoma cell lines with these mutations and even in several other neuroblastoma samples, suggesting that ALK could be a powerful target for anti-cancer medications, Mossé adds.
“We’ve found that ALK is expressed in basically all neuroblastomas, even though it shouldn’t be,” she says.
Although ALK’s exact function remains unknown, scientists speculate that the gene plays an important role in cell growth, since ALK appears primarily during neural development and its expression largely stops after birth.
Clinical trials soon?
The new work supports previous research, on patients with lymphoma and lung cancer, suggesting ALK can act as an oncogene, a gene that has the potential to cause a normal cell to become cancerous.
Because pharmaceutical companies already were exploring the gene as a potential drug target for these diseases, new treatments for neuroblastoma could be on the fast track as well.
“At least one small-molecule ALK inhibitor is already in clinical trials,” Mossé says. “In the lab, [these inhibitors] have shown a profound effect. Now we’re working with the company to start clinical trials for neuroblastoma in the next six months.”
In the meantime, her team is working to adapt their results into improved diagnostic tests for neuroblastoma.
A genetic test for abnormal ALK will be offered to all children and families with neuroblastoma, along with family-planning counseling in the case of positive results.
The test also will determine which at-risk patients might need additional monitoring, since catching neuroblastoma early greatly improves the odds of survival, Mossé says.