Researchers at the University of Michigan Rogel Cancer Center have identified a novel treatment approach to an aggressive type of pediatric brain cancer, using therapies already approved to treat cancer.
“Our findings have immediate translational potential, which is very exciting,” said senior study author Maria Castro, Ph.D., R. C. Schneider Collegiate Professor of Neurosurgery and professor of cell and developmental biology at Michigan Medicine.
The team developed a mouse model of pediatric glioma with a histone mutation called H3.3-G34. The mutation is seen in about half of children with brain cancer. The mouse model allowed researchers to study the tumor’s biology in the presence of a functional immune system, revealing a promising outlook for long-term survival.
Tumors with the H3.3 mutation have a defect in how they repair DNA. This means the tumors are more responsive to radiation therapy, a treatment that works by damaging DNA. Combined with surgery, radiation has been the standard therapy for pediatric high-grade glioma.
The finding also suggested synergizing the effect by pairing radiation with a small-molecule inhibitor that even further impairs the DNA damage response. They tested this in both human cell cultures and mice using pamiparib, a PARP inhibitor that has been shown to cross the blood-brain barrier.
“If we combine small molecules that inhibit the repair of DNA with radiotherapy, the radiation becomes much more effective. We saw this approach not only improved median survival of mice, but also gave us long term survivors,” said Santiago Haase, Ph.D., a postdoctoral fellow in the Castro-Lowenstein lab. Haase is first author on the paper, published in the Journal of Clinical Investigation.
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