Meningiomas are the most common
brain tumor, striking 170,000 Americans every
year. Until recently they have largely been mysteries to
medicine. Part of that mystery was solved earlier this
year by a team of researchers led by Dr. Murat Günel,
Professor of Neurosurgery, Neurobiology, and Genetics.
Their discoveries promise to alter clinical treatment of
patients afflicted with these tumors. The research was
funded by a generous grant from the Gregory M. Kiez
and Mehmet Kutman Foundation, which allowed the
formation of the Brain Tumor research program at Yale.
Unlike more familiar brain tumors such as glioblastomas
and medulloblastomas, which are ferociously malignant, fast
growing, and usually fatal, meningiomas grow slowly and are
benign 80 percent of the time. Nevertheless they can invade
or pressure critical parts of the brain, causing neurological
damage or stroke. They are typically treated through the
invasive options of surgery or radiation. “There have been no
chemotherapy options,” Dr. Günel said, “because the genetic
make-up of meningiomas has not been understood. Before our
work, we largely did not know how these tumors happened.”
Previous research had linked about half of meningiomas to
a mutation of the gene NF2, though the mechanism remained
unclear, as did the cause of all other meningiomas. To remedy
this, Dr. Günel and his team took advantage of what he calls
“the revolution of genomic technologies,” carrying the cuttingedge
research methods to the care of his patients after surgery.
For a brain surgeon, he said, the most frustrating aspect is not
to be able to cure a patient of their disease after a successful
surgery. To gain a better insight into the genetic make-up of
brain tumors in an attempt to achieve cure, his team, starting
with Victoria Clark, a Yale MD/PhD student, genotyped and
exome sequenced 300 meningioma tumors.
“We found that mutations of five genes explain around
85 percent of all benign meningiomas,” Dr. Günel said.
The roles played by four of the genes—AKT1, SMO, KLF4,
and TRAF7 (the fifth is NF2)—were previously unknown.
Further, the researchers learned that the tumors generated
by these mutated genes grow in different parts of the brain.
Tumors associated with NF2, for instance, tend to form in
the cerebral hemispheres, whereas tumors associated with the
other four genes group in areas along the front skull base.
“Thus, for the first time,” wrote the team in Science (January
24), where the findings were announced, “it seems that the
simple evaluation of a patient’s MRI can offer insight into the
molecular profile of the meningioma.”
This genetic mapping and the resultant diagnostic insights
will open the way for individualized treatments that target
each type of meningioma. For instance, SMO mutations
have been found in basal cell skin carcinoma and brain
medulloblastomas. “There is already an FDA-approved drug
for basal cell carcinoma,” Dr. Günel said, “so we are testing
it in the lab using cell cultures to see if the same drug has an
effect on SMO mutant meningiomas.” If so, he expects to begin
clinical trials on patients with these tumors early in 2014.
That’s good news, but SMO mutations account for less
than five percent of meningiomas. NF2 mutations, on the
other hand, are implicated in half of meningiomas but are
not yet targeted by an FDA-approved drug. That’s especially
troubling since NF2 meningiomas are also the most likely to
become malignant.
“But there are certain clear targets downstream of NF2 that
are activated when NF2 is lost,” Dr. Günel explained. “In our
lab we are now testing experimental medications aimed at
those.” They hope to finish the testing on cell cultures within a
year and then move to clinical trials. Meanwhile researchers at
other institutions are in the midst of phase-II trials for a drug
aimed at NF2 tumors in other types of cancer. Dr. Günel’s team
will incorporate those results into their studies. “There’s a tidal
wave of cancer research that is raising all of us,” he said. “We’re
all learning from each other in the different cancer disciplines.”
The Yale researchers found a TRAF7 mutation in about
a quarter of the meningiomas. Almost nothing is known
about this gene, but wherever the team found its mutated
form, they also found a better-known partner—either KLF4,
a transcription factor, or AKT1, which activates the PI3K
pathway. The PI3K pathway is well-known and has been
implicated in cancer; several medications against it are now
in clinical trials. Since TRAF7 is unstudied, Dr. Günel and his
team are hoping to track its mutation through its co-existence
with AKT1 and the PI3K pathway.
“It’s interesting that they co-mutate,” he said. “So what we
are testing is, can a PI3K inhibitor affect that TRAF7 tumor?
If the inhibitor breaks one leg of the cancer, can the cancer still
run or does it stop?” If the PI3K inhibitor brakes the TRAF7
meningioma, the next step will be to figure out the downstream
signaling mechanism of TRAF7. Because all this is unknown
territory, Dr. Günel expects that exploring this gene will
require more time than the other mutations associated
with meningiomas.
Still, Dr. Günel’s team has described the genetic landscape
Unlike more familiar brain tumors such as glioblastomas
and medulloblastomas, which are ferociously malignant, fast
growing, and usually fatal, meningiomas grow slowly and are
benign 80 percent of the time. Nevertheless they can invade
or pressure critical parts of the brain, causing neurological
damage or stroke. They are typically treated through the
invasive options of surgery or radiation. “There have been no
chemotherapy options,” Dr. Günel said, “because the genetic
make-up of meningiomas has not been understood. Before our
work, we largely did not know how these tumors happened.”
Previous research had linked about half of meningiomas to
a mutation of the gene NF2, though the mechanism remained
unclear, as did the cause of all other meningiomas. To remedy
this, Dr. Günel and his team took advantage of what he calls
“the revolution of genomic technologies,” carrying the cuttingedge
research methods to the care of his patients after surgery.
For a brain surgeon, he said, the most frustrating aspect is not
to be able to cure a patient of their disease after a successful
surgery. To gain a better insight into the genetic make-up of
brain tumors in an attempt to achieve cure, his team, starting
with Victoria Clark, a Yale MD/PhD student, genotyped and
exome sequenced 300 meningioma tumors.
“We found that mutations of five genes explain around
85 percent of all benign meningiomas,” Dr. Günel said.
The roles played by four of the genes—AKT1, SMO, KLF4,
and TRAF7 (the fifth is NF2)—were previously unknown.
Further, the researchers learned that the tumors generated
by these mutated genes grow in different parts of the brain.
Tumors associated with NF2, for instance, tend to form in
the cerebral hemispheres, whereas tumors associated with the
“There’s a tidal wave of cancer research that is raising all
of us. We’re all learning from each other in the different cancer disciplines.”
for 85 percent of these tumors. Drugs that target each specific
mutation are on the way and will soon give people with
meningiomas the option of personalized chemotherapy, which
will be more effective and also less invasive than the current
options of surgery and radiation. In fact, Dr. Günel and his
colleagues at Yale Cancer Center now have a weekly Precision
Medicine Tumor Board, in which they discuss the use of
targeted therapies based on the individual genomic make-up
of various cancers.
The genetic mapping of benign meningiomas was relatively
easy to solve, noted Dr. Günel, because they have far fewer
genetic abnormalities than cancerous tumors. “But the good
thing,” he adds, “is that it turns out there are not infinite ways
that nature creates cancer. There are only a limited number of
genes involved.” The new genomic technologies are tracking
these down, followed quickly by new drugs that target them.
For a brain surgeon, the biggest target is the most deadly
brain cancer, glioblastoma multiforme (GBM). Dr. Günel is
optimistic. “We have some really exciting findings,” he said.
“Next time, I hope we can talk about curing some of the GBMs.”