Researchers at the University of Michigan have developed a new tool to test potential treatments for pediatric brain cancer.
A team led by Maria Castro and Pedro Lowenstein, professors of neurosurgery and cell and developmental biology, has created a mouse model which harbors all the genetic alterations found in pediatric brain tumors. Using the new model, the researchers have replicated pediatric brain tumors in mice that will allow the mice to serve as test beds for new pharmaceuticals and immunotherapies designed to shrink children’s brain tumors — specifically high-grade glioma, which is an aggressive and malignant type of brain tumor.
Unlike adult with brain tumors, children cannot receive radiation therapy because children’s brains have a highly impermeable blood-brain barrier, meaning most chemotherapeutic agents are not responsive.
Carl Koschmann, a cancer specialist at the UM Mott’s Children’s Hospital and the first author of the study, explained children with high-grade glioma are even more challenging to treat.
“Pediatric high-grade glioma remains very difficult to treat effectively, and most children will not survive beyond two years of receiving this diagnosis,” Koschmann said. “The difference is that some of the tools that work for other cancers, including surgery and radiation, are difficult to use on a child’s brain. Chemotherapy works for some brain tumors, but high-grade glioma is resistant to almost all chemotherapy.”
The inability to use chemotherapy has led to the exploration of several alternative methods of treatment, including DNA damaging drugs.
DNA-damaging drugs have existed for many years and are used for various purposes in adult patients, but University researchers have found that, when used on the new model mice, they shrank the size of their brain tumors.
One-third of children with brain tumors have a mutation in the ATRX protein that already helps repair damage to the cells — Castro said by furthering that damage to the cells with the drugs, they were able to kill it all together.
“If you have bad mutations, your DNA is unstable, so you treat it with a drug that induces further damage, and the cell dies more readily, that means you are going to be able to treat these children in a better way,” he said.
Third-year medical student Flor Mendez worked on the research project, and said she thought the progress they have made will help future treatment.
“Our work on the role of ATRX mutations, prevalent in pediatric GBM, uncovered that ATRX deficient tumors have a defect in a mechanism of DNA repair which makes them more sensitive to therapies that induce DNA damage to destroy tumor cells,” she said. “This knowledge will help guide the development of improved therapies for patients with ATRX mutations.”
Other University researchers within the same lab have also been working to develop new treatment techniques through immunotherapy, which the mouse model can also be used for. That form of treatment trains the immune system to recognize and attack cancer cells, which Castro said is incredibly difficult due to the complex nature of cancer cells.
“Tumors have mechanisms by which they can hijack the immune system, they trick the immune system and they become kind of invisible so what you need to do is unmask it,” Castro said. “And you need to be able to allow the immune system to be able to see the tumor as an invader in a way as they would see a bacteria or a virus.”
The new mouse model allows for developments in immunotherapy because the model has a fully functioning immune system Castro said. Most models currently used for research take tumors from human patients to prepare cells for testing, but these cells are not compatible with animal models. Therefore, researchers cannot test immunotherapeutic strategies.
Lowenstein said he finds immunotherapy appealing as a scientific avenue for treatments for a variety of reasons.
“The ability to harness the power of the immune system to treat cancer is a very attractive treatment modality for these devastating childhood brain cancers, as it could provide an effective, safe and non-invasive treatment strategy,” Lowenstein said.