Targeting a rare secondary cancer in children

Date:
September 28, 2021
Source:
University of Colorado Anschutz Medical Campus
Summary:
Known as pediatric radiation-induced high-grade gliomas (RIGs),
this specific type of brain tumor is caused by cranial radiation
therapy for other cancers, most often brain cancers. They account
for nearly 4% of all childhood brain tumor deaths, but there have
not been many studies on RIGs and how to treat them.



FULL STORY ==========================================================================
It's one of the most heartbreaking things Adam Green, MD, sees as a
pediatric oncologist: children who beat their cancer, only to see an
incurable brain tumor arise five years later.


========================================================================== "It's especially tragic because generally by this point they're
teenagers, or they're young adults who are trying to move forward with
their lives after dealing with cancer and still may be dealing with some
of the aftereffects of the treatments," says Green, a CU Cancer Center
member who practices at Children's Hospital Colorado. "Then suddenly
they get this secondary tumor that's incurable, and most of them die
within a year. It's really horrible." A rare killer Known as pediatric radiation-induced high-grade gliomas (RIGs), this specific type of
brain tumor is caused by cranial radiation therapy for other cancers,
most often brain cancers. They account for nearly 4% of all childhood
brain tumor deaths, but there have not been many studies on RIGs and
how to treat them.

Working with patient samples collected over the past decade by the
Morgan Adams Foundation Pediatric Brain Tumor Research Program at the University of Colorado School of Medicine, Green and graduate student
John DeSisto spent the past four years analyzing RIGs, using DNA and
RNA sequencing to discover how they differ from "de novo" gliomas --
or gliomas that develop not in response to cranial radiation. Green
and his collaborators -- including several CU Cancer Center members,
as well as scientists from St. Jude Children's Research Hospital in
Memphis and the Children's Cancer Center in Hamburg, Germany -- were
searching for ways to prevent RIGs from forming, as well as methods to
treat them once they arise. Their research was published September 20
in the journal Nature Communications.

"We found that the mutations that occur in these tumors are pretty
different than the mutations that characterize de novo pediatric high
grade gliomas. It seems to be a different biological process that is
driving these to develop," Green says.



==========================================================================
The role of DNA repair Through RNA sequencing, Green and his team
examined more than 30 tumor samples, ultimately splitting them into two subgroups based on which genes were turned off and on in the samples. One
of the subgroups showed an impaired ability to repair DNA, leading the researchers to hypothesize that patients with conditions that cause
impaired DNA repair may be at higher risk for developing RIGs once they
are exposed to radiation. If those specific weaknesses can be detected
early, he says, doctors could provide alternative treatments or monitor patients more closely after radiation to see if RIGs develop.

"What we think is that some patients may have problems with their
DNA that are not enough to cause cancer on their own, but when they
get exposed to radiation, that puts them at much higher risk," he
says. The reason the tumors take years to grow is because "radiation
can damage DNA, but for that transformation to happen from a normal
cell that's damaged by radiation to a cancer cell takes a long time,"
he adds. "If DNA is damaged, and that cell isn't as good at repairing
its own DNA, then additional errors in the DNA continue to happen
over time, until eventually the cell can transform into a tumor cell."
Creating a consortium and looking at treatment for a longer life The researchers also tested a number of FDA-approved chemotherapy drugs on
both RIG subgroups, finding that there are certain drugs that seem to
be effective against RIGs. Going forward, they plan to develop animal
models to further test the drugs, and eventually to develop a clinical
trial in humans to identify the best way to treat the tumors.

"We think that the treatments that work for the two different types
of these high-grade gliomas may be very different between RIGs and de
novo tumors," Green says. "If we go into a clinical trial, it would be important to do it specifically for RIG. But RIGs are rare, so we're
trying to get other investigators around the world interested in studying
these tumors and get a research consortium going that could help with
this lab work, help get more patient samples, and then, eventually, all cooperate on a clinical trial." Ultimately, Green hopes the research
will lead to better treatments for patients either at higher risk of
RIGs or who have developed RIGs, so that the number of patients dying
young from these secondary tumors starts to decrease.

"There are other types of secondary cancers in kids that come from
their prior cancer treatments, like leukemias that that occur because
of chemotherapy or sarcomas that happen because of radiation," he
says. "Those are often curable, but RIGs are not. Our goal is to be
able to treat these effectively so that patients can have more time
with a good quality of life. That even if they get a secondary cancer
like this, we can cure it so they can live a long productive life." ========================================================================== Story Source: Materials provided by University_of_Colorado_Anschutz_Medical_Campus. Original written by Greg Glasgow. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. John DeSisto, John T. Lucas, Ke Xu, Andrew Donson, Tong Lin, Bridget
Sanford, Gang Wu, Quynh T. Tran, Dale Hedges, Chih-Yang Hsu,
Gregory T.

Armstrong, Michael Arnold, Smita Bhatia, Patrick Flannery, Rakeb
Lemma, Lakotah Hardie, Ulrich Schu"ller, Sujatha Venkataraman,
Lindsey M.

Hoffman, Kathleen Dorris, Jean M. Mulcahy Levy, Todd C. Hankinson,
Michael Handler, Arthur K. Liu, Nicholas Foreman, Rajeev Vibhakar,
Kenneth Jones, Sariah Allen, Jinghui Zhang, Suzanne J. Baker,
Thomas E.

Merchant, Brent A. Orr, Adam L. Green. Comprehensive
molecular characterization of pediatric radiation-induced
high-grade glioma. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021-25709-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210928121321.htm

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