Exploring pathways for
treating TIHGG
CANCER
Cure as Cause
Five or ten years out from
treatment with traditional
chemotherapy and radiation
for pediatric cancers like
medulloblastoma, lymphoma
and leukemia, some patients
develop a secondary cancer
called a treatment-induced
high-grade glioma, or TIHGG.
Right now, there’s no way to
treat them. Working in The
Morgan Adams Foundation
Pediatric Brain Tumor Research
Program, Pediatric Oncologist
Adam Green, MD, wants to
change that. TIHGG tumors, they don’t respond to it. Surgery is
also not a viable curative option, since TIHGG cells
invade healthy tissue. Surgeons must remove a
large part of a patient’s brain to remove the tumor,
and when they’ve attempted, the tumors return in
another part of the brain.
“TIHGGs are not a recurrence,” says Dr. Green.
“They’re aggressive, invasive secondary tumors
that have received little research attention, given
that they cause about 4 percent of pediatric brain
tumor deaths. That’s a significant number, since
brain tumors are already the most common cause
of pediatric cancer deaths.” A mutation that may increase a patient’s risk
for a secondary tumor doesn’t warrant altering
treatment independently. Providers would need
to know that the mutation is responsible and how
likely it is that it would cause a secondary tumor.
The most effective treatment for tumors is often
radiation, but because radiation most likely causes
Evaluating risk through
DNA analysis
Dr. Green’s team is studying patient germline
DNA to understand what consistent factor could
make patients susceptible to TIHGG tumors.
They recently found a clue: a defect in DNA repair.
By studying tumors in Children’s Colorado’s
tumor bank from the last 20 years, Dr. Green’s
team has also found that TIHGG tumors fall into
two groups based on expression of RNA. One of
these groups appears to be driven by NF-κβ, a
major oncogenic pathway.
“All cancer pathways have a normal function,
but in patients with cancer, they’re usually too
active or don’t respond to inhibitory signals,” says
Dr. Green. “If NF-κβ is driving the TIHGG in one of
these groups, it could be disinhibited.”
Dr. Green’s team is performing cell line tests to
learn how TIHGG tumors respond to proteasome
inhibitors, an FDA-approved targeted therapy.
Their research has shown that proteasome
inhibitors are highly effective at killing TIHGG
cells driven by NF-κβ.
The team’s next step will be testing this
treatment on animal models. But developing
models is especially challenging because it
involves understanding the situation in which a
secondary tumor develops in humans and then
replicating it in mice.
They’re also combining efforts with St. Jude
Children’s Research Hospital to gain access to
more samples and understand what drives
TIHGG tumors.
“When a child who has been cured of cancer
develops a secondary tumor, it’s tragic,” says
Dr. Green. “These tumors have been understudied,
but our core facilities, scientific know-how and
translational experience uniquely position us to
advance this research. We hope we can make a
difference.” ●
“Though we believe many people have this
mutation, it only appears to be harmful for some,
including those who get an aggressive cancer
treatment – like radiation or chemotherapy,”
says Dr. Green.
Radiation and chemotherapy damage DNA. If a cell
can’t repair itself, that can put a patient at risk for a
tumor, in this case, a secondary TIHGG tumor.
“If this mutation increased risk by a few percentage
points, that may not be worth a potentially less
effective treatment for a patient’s initial cancer,”
says Dr. Green. “However, if it’s a 75 percent
increase in risk, then that may be worth it.”
Left: Adam Green, MD, and senior research associate Andrew Donson study a sample from our tumor
bank, which contains decades of tumor samples gathered from patients at Children’s Colorado.
Right: In the past, DNA and RNA sequencing could take years. Today, our researchers can complete
sequencing in hours using advanced sequencing technology like this NovaSeq from Illumina.
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NEW CONSTELLATIONS
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