Brain tumors are notoriously difficult to treat, and are not all alike. Each subtype of tumor contains different mutations that may affect growth or resistance to certain treatments.
Researchers have discovered that mutations in gliomas, the most common type of brain tumor, grant resistance to radiation therapy by activating the machinery inside tumor cells that repair DNA damage. Blocking DNA repair with small molecules can render such tumors in mice vulnerable to radiation again (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aaq1427).
About half of all gliomas have a mutation in the gene coding for isocitrate dehydrogenase 1 (IDH1). This IDH1 mutation boosts methylation of proteins called histones in chromosomes, inducing epigenetic changes to the tumor’s genome. Patients with this mutation usually have a better prognosis, with survival rates of about 7–10 years, compared with 18–20 months for more aggressive gliomas. When this mutation is paired with others that inactivate two other genes, ATRX and TP53, the result is a tumor that is also hard to treat.
A 35–person team led by Maria G. Castro and Pedro R. Lowenstein of the University of Michigan spent five years studying the effects of these mutations. They examined DNA-methylation patterns and gene transcription and translation in mutant tumor cells grown in the lab and in mice genetically engineered to bear the cancer-causing mutations. The researchers found that the epigenetic changes in glioma cells caused by these mutations enhance the cells’ response to DNA damage, stabilizing the tumor genome.
Tumors with stable genomes tend to grow slowly and take longer than aggressive tumors to become malignant, Lowenstein says. The mutation also explains why radiation treatment is ineffective on this subset of gliomas: Radiation creates double-stranded breaks in DNA, but these mutant tumor cells can rapidly repair such damage.
In search of a way to reverse the tumors’ radiotherapy resistance, the team tested two compounds, KU-60019 or AZD7762, that inhibit DNA repair on mice bearing tumors with this set of mutations. When used in concert with radiation treatment, the compounds prolonged the survival of mice and decreased tumor size.
“We think we identified a very important aspect of this mutation’s function that helps explain why these tumors evolve slower than other gliomas,” Lowenstein says. “And in doing so, we found a way to counteract the effects of the mutation.”
C. Ryan Miller, a neuro-oncologist at the University of North Carolina at Chapel Hill, calls the study “stellar, innovative work” and highlights the identification of two potential drug targets for future clinical trials. He thinks the findings could be translated into a personalized medical treatment for brain-cancer patients with tumors carrying this set of mutations.
Although blocking DNA repair could have negative side effects, Lowenstein points out that in a treatment, such compounds would be administered only in conjunction with radiation therapy, not continuously. And some DNA repair-blocking drugs have already been approved by the US Food and Drug Administration for the treatment of some cancers.
The team continues to study the effects of these tumor mutations, including how the tumor cells interact with the immune system. Lowenstein says that they are also working toward a clinical trial of the combination therapy in patients with gliomas carrying these mutations.