A. Thomas Look, MD, senior author of the study
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
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
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
The research was supported by grants from the National Institutes of
Health, the Friends for Life Neuroblastoma Fund, the Children's Oncology
Group, Alex's Lemonade Stand Foundation, and the American Lebanese
Syrian Associated Charities of St. Jude Children's Research Hospital.
The co-authors of the study are Nathaniel Gray, PhD, Takaomi Sanda,
MD, PhD, William Luther II, Yebin Ahn, Jianming Zhang, PhD, Wenjun Zhou,
and Lisa Diller, MD, of Dana-Farber; Matthew Meyerson, MD, PhD, Megan
Hanna and Heidi Greulich, PhD, of Dana-Farber and the Broad Institute of
Harvard and MIT; Gary Gilliland, MD, PhD, and Dr. Stefan Frohling, MD,
of Brigham and Women's Hospital, Boston; Wendy B. London, PhD, and
Patrick McGrady of the University of Florida, Gainesville; Liquan Xue,
PhD, Thomas Webb, PhD, and Stephan Morris, MD, of St. Jude Children's
Research Hospital, Memphis, Tenn.; and Vlad Gregor, PhD, of ChemBridge
Research Laboratories, San Diego.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National