Scientists at Johns Hopkins have linked a stem-cell
gene called Notch2 to a portion of one of the most common
childhood brain cancers, opening the door to tailored
therapies that block the gene's tumor-promoting
ability.
The gene, whose pathway is known to be an important
factor in regulating brain stem-cell growth and survival,
has been studied in fruit flies for almost a century. The
research team at the Johns Hopkins
Pathology
Department and
Kimmel
Cancer Center found that a protein made by the gene
promotes cancer cell growth by 27 percent in a childhood
brain tumor called medulloblastoma. Their studies, reported
in the Nov. 1 issue of Cancer Research, also
revealed that children with high Notch2 gene activity fared
worse in the course of their disease than those with less
activity in Notch2.
The researchers report that a drug first developed for
Alzheimer's disease called DFK-167, which blocks activation
of all Notch proteins, reduces growth of cancerous cells in
culture by 80 percent, although unwanted side effects and
dosing problems may make it a poor choice for treating
human brain cancer. But the investigators are testing more
potent drugs of the same class and developing new ones that
block only the Notch2 pathway.
No clinical trials with any drug have yet been
planned, the researchers emphasize.
Scientists say that gene amplification — a
process in which cells make too many copies of a gene
— is one of the most reliable indicators of a gene's
importance to cancer development. The Johns Hopkins team
found Notch2 amplified in six of 40 medulloblastomas and
other similar brain tumors.
"Just like genetic mutations, amplifications are
long-lasting DNA mistakes, as opposed to transient changes
in the production of proteins and other gene products,"
said Charles Eberhart, assistant professor of pathology.
"Finding amplification of Notch2 is a smoking gun tying it
to the development of these brain tumors."
In their study, the Johns Hopkins scientists compared
levels of a protein marker for Notch2 gene activity to the
survival of 35 medulloblastoma patients. Of 11 patients
with high levels, seven died; of 24 patients with no
detectable protein, only six died.
Standard surgery and radiation for medulloblastoma
cures approximately 60 percent of children but often
results in many neurological and learning
disabilities.
"We'd like to develop a drug that only affects the
Notch2 pathway, since blocking other members of the Notch
family may actually have the opposite effect and encourage
cancer growth," said Xing Fan, first author of the study
and postgraduate fellow.
In 25 of 30 of the medulloblastomas it studied,
Eberhart's team also found lower levels of Notch1, compared
to Notch2, gene products. Notch1 proteins normally provide
a brake on growth of medulloblastoma cells, and blocking
their activation would cancel out some of the drug's
effects. "The net effect of any drug will depend on how
much of each Notch1 and Notch2 is present, and since we
found more Notch2, we think the scale can be tipped toward
stopping the cancer," Eberhart said.
This research was funded by the Children's Brain Tumor
Foundation, National Institute of Neurological Disorders
and Stroke, and National Cancer Institute. Other JHU
research participants are Irina Mikolaenko, Ihab Elhassan,
Xing Zhi Ni, Yunyue Wang and Douglas Ball.
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