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Blocking DNA repair restores sensitivity of brain tumors to treatment in mice

Cancer cells that harbor the IDH1 disease mutation were taken from mouse tumors and grown in a petri dish. Castro lab, University of Michigan

Cancer is caused by cells that grow and divide uncontrollably. Gliomas are a deadly type of cancer that starts in brain cells called glial cells. Studies have shown that mutations in the isocitrate dehydrogenase 1 (IDH1) gene are an early event that helps drive many gliomas. These tumors also often develop mutations in genes called TP53 and ATRX.

Glioma patients whose tumors have mutations in IDH1 are typically younger and live longer than those whose tumors have the normal version. However, the vast majority of these gliomas still turn into more aggressive, dangerous glioblastomas over time.

To explore ways to treat gliomas with IDH1 mutations, a team led by Drs. Maria G. Castro and Pedro R. Lowenstein at the University of Michigan genetically engineered mice to grow brain cancer cells with the disease-causing mutations in IDH1 along with mutations in TP53 and ATRX. The research was supported primarily by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), along with several other NIH components. Results were published on February 13, 2019, in Science Translational Medicine.

Like patients with the IDH1 mutation, genetically engineered mice with the mutation lived longer than mice whose tumors had normal IDH1 while harboring the mutations in TP53 and ATRX.

The researchers found that the IDH1 mutation made glioma cells less aggressive. The cells divided at a lower rate than those without the mutation and were much less likely to trigger tumor growth when implanted into mouse brains.

Further experiments showed that IDH1 mutations led to epigenetic changes—DNA modifications that don’t change the DNA sequence itself. These changes increased the manufacture of proteins known to repair damaged DNA.

The IDH1-mutated tumors were resistant to ionizing radiation, a treatment that normally kills cells by damaging DNA. These results suggest that mutant IDH1 helps cells repair damaged DNA more efficiently. That may slow tumor growth but also make the tumors more resistant to radiation treatment.

The researchers found that they could extend the lives of mice with the mutant IDH1 tumors by exposing them to radiation while also injecting them with one of two compounds designed to block DNA repair. In contrast, treating these mice with either radiation or either of the drugs alone had no effect.

Several of the findings in mice were also seen in human gliomas grown in petri dishes. The researchers are now planning a Phase 1 clinical trial to test the safety and efficacy of the combination therapy strategy developed in this study.

“Every year thousands of people are diagnosed with brain cancer and have little hope for long-term survival,” Castro says. “Our team’s mission is to find life-saving treatments for these patients. The results from this study could be a blueprint for extending, if not saving, the lives of many patients.”