Childhood brain tumors are the second-most frequent malignancy of childhood and the most common form of solid tumor. Tumors of the central nervous system comprise 22 percent of all malignancies occurring among children up to 14 years of age and 10 percent of tumors occurring among 15-19-year-olds.
A lack of treatment options keeps survival rates low. Unlike adults with brain cancer, children cannot receive radiation therapy, so physicians must rely on medications and other strategies. In addition, because of either the effects of the tumor or the treatment required to control it, survivors of childhood brain tumors often have severe neurologic, neurocognitive and psychosocial sequelae.
But children with brain cancer may soon get some help from mice with the same disease.
Researchers from University of Michigan Medical School and their colleagues have developed a novel brain tumor model in mice. The mice have the same genetic problems as those seen in many children with the most dangerous forms of brain cancer, so the mice should be able to serve as a new test bed for treatments aimed at shrinking children's tumors.
To create the new mouse model of children's brain cancer, the researchers caused a mutation that occurs in many tumors and used special stains to distinguish on a microscopic level the healthy brain tissue and the areas where the mutation took hold and a tumor arose. And, unlike previous attempts by others, the model generated at U-M has a fully functional immune system, which makes it even more like the children the mice mimic.
In addition to developing the new genetically engineered mouse model for the form of cancer called glioblastoma multiforme (GBM), the researchers made a key discovery about brain tumor biology via the mice. Their work focuses on a protein called ATRX and its role in helping cells repair damage to DNA.
About one-third of children and young adults with brain cancer have ATRX mutations in their cancer cells. Ironically, the researchers also showed that if they treated the mice's tumors with drugs that damage DNA, they could actually shrink tumors more effectively and improve survival.
This genetic instability accelerated tumor growth and reduced the survival of mice that went without treatment. Using a special genetic technique that introduced the same mutation in mice, soon after birth, the scientists were able to generate brain tumors that made less of the ATRX protein. When the cancer cells didn't make enough ATRX, the cells couldn't join together the two ends of a broken DNA strand.
According to U-M children's cancer specialist Carl Koschmann, M.D., the first author of the study, this tumor model is exciting because it mimics the developmental environment of a pediatric or adolescent human brain tumor. Koschmann knows new treatments are desperately needed for pediatric GBM patients, because fewer than 20 percent of children diagnosed with GBM will survive five years.
Currently, treatment for pediatric patients is based on a regimen designed for adult patients with GBM, which are very different tumors at the molecular level. The new mouse model is a great step toward developing targeted therapies to specific changes found in pediatric and adolescent GBM.
