Oncology researchers studying gene mutations in the childhood cancer neuroblastoma are refining their diagnostic tools to predict which patients are more likely to respond to drugs called ALK inhibitors that target such mutations. Removing some of the guesswork in diagnosis and treatment, the researchers say, may lead to more successful outcomes for children with this often-deadly cancer.
“Some mutations are more important than others,” said Yaël P. Mossé, MD, a pediatric oncologist at The Children’s Hospital of Philadelphia in Pennsylvania, and a co-leader of the new study published in Cancer Cell (2014; doi:10.1016/j.ccell.2014.09.019). “By integrating biochemistry into our clinical strategies, we can better match a patient’s specific ALK-mutation profile with an optimum treatment.”
“Understanding the specific mutations that trigger signals in cell receptors to stimulate cell growth will help us identify biomarkers for specific subtypes of neuroblastoma,” said study co-leader Mark A. Lemmon, PhD, professor and chair of Biochemistry and Biophysics at Penn.
The new findings will provide crucial data for a pivotal phase 3 study for patients with ALK-driven high-risk neuroblastoma. This trial will be conducted through the Children’s Oncology Group (COG), a cooperative research organization encompassing more than 250 pediatric cancer programs in North America. The COG is supported by the National Cancer Institute.
A solid tumor of the peripheral nervous system, often appearing in the chest or abdomen, neuroblastoma is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children, with cure rates lagging behind those for other pediatric cancers. Neuroblastoma is complex, with many subtypes of the disease.
The current study concentrates on various mutations in ALK, the anaplastic lymphoma kinase gene.
Crizotinib is a molecule that inhibits the ALK protein when it is switched on by some ALK gene mutations, and it has a stronger anticancer effect against some ALK mutations than in others.
A previous study found that higher doses of crizotinib would be necessary for children with one mutation compared to another mutation. This knowledge could help oncologists define the correct dosage before an initial treatment.
The current study explored the full spectrum of neuroblastoma, analyzing DNA from a COG tumor bank drawn from nearly 1,600 patients. The team discovered ALK mutations in 8% of the tumors, with a higher rate among tumors from older patients and those with high-risk neuroblastoma. The researchers also investigated which ALK mutations were more sensitive to crizotinib in cell cultures.
“Our computational approach can predict which ALK mutations are activating—that is, which ones drive cancer—and just as importantly, which mutations are not,” said Radhakrishnan.
“This will give oncologists a way to avoid overtreating or undertreating each patient, by knowing whether crizotinib or similar ALK inhibitors will be necessary and effective,” added Lemmon.
They commented that their analytical method also holds great promise in predicting the behavior of new ALK mutations not yet discovered.