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A Common Brain Cancer Control Project NIH-funded researchers have shown how gliomas can be treated with radiation and drugs blocking DNA repair. Courtesy of Castro Laboratory, Michigan Medicine, Ann Arbor
In a study on human mice and brain tumors, Ann Arbor, from the University of Michigan, researched new treatments by exploring why some patients with glioma live remarkably longer than others. . The results suggest that tumor cells in some patients are less aggressive and much better at repairing DNA than others, but are difficult to destroy by radiation. The researchers then showed that the combination of radiation therapy with anticancer drugs designed to block DNA repair could be an effective treatment strategy. The study was funded by the National Institutes of Health.
The researchers focused on low-grade gliomas carrying a mutation causing disease in a gene called isocitrate dehydrogenase 1 (IDH1), which encodes a protein known to help cells produce energy. . This mutation is found in about 50% of cases of low grade primary gliomas, common form and lethal brain tumor. Patients with glioma whose tumors have mutations in IDH1 are generally younger and live longer than tumors with the normal gene. These tumors also often have mutations in genes called TP53 (a tumor suppressor gene) and ATRX (a DNA-protein complex remodeling gene).
"Each year, thousands of people are diagnosed with brain cancer and have little hope for long-term survival," said Maria G. Castro, Ph.D., professor of neurosurgery at Michigan Medicine and author main document published in Science Translational. Drug. "Our team's mission is to find life-saving treatments for these patients. The results of this study could be a model for extending or even saving the lives of many patients. "
The researchers reconstructed patients' tumors using mice to develop brain cancer cells bearing the mutations responsible for the disease in IDH1, as well as mutations in TP53 and ATRX. Like the patients, these mice lived longer than the control mice whose tumors were programmed to have a normal IDH1 while retaining the mutations in TP53 and ATRX.
When the research team examined the tumors, she found that the IDH1 mutation made the glioma cells less aggressive. The cells split at a lower rate than the controls and were much less likely to trigger tumor growth during implantation in the mouse brain.
They also discovered that the mutation IDH1, in the presence of mutations in TP53 and ATRX, made the tumors resistant to ionizing radiation, a treatment that kills cells often by damaging the DNA. For example, radiation exposure prolonged the life of mice implanted with control tumors, but had no effect on mice implanted with IDH1 mutant cells.
Other experiments have provided a possible explanation for this resistance. The results suggest that the disease-causing mutation altered the activity of IDH1, triggering a cascade of chemical reactions that altered cancer cell genes to increase the production of proteins known to repair damaged DNA.
"Our results show that the metabolic changes caused by the IDH1 mutation reprogram cancer cells in the brain," said Dr. Castro.
These results led the researchers to formulate and test a new combination therapy. They discovered that they could prolong the life of mice with mutant IDH1 tumors by exposing them to radiation while injecting them with anticancer drugs designed to block DNA repair. In contrast, treatment of these mice with radiation or one of the drugs alone had no effect. Several of the results observed in mice have also been observed in human gliomas grown in Petri dishes.
"These results could impact many younger glioma patients with low-grade tumors, either by" healing "them or by extending their lives," said Jane Fountain, Ph.D., Program Director. at the National Institute of Diseases and Stroke NIH. "The preclinical model developed by Dr. Castro's team will be extremely valuable to cancer researchers. It closely reflects the human disease. "
Dr. Castro's team has begun to plan a Phase 1 clinical trial that will test the safety and efficacy of the combination therapy strategy described in this study.
This article has been republished from material provided by the NIH. Note: Content may have changed for length and content. For more information, please contact the cited source.
Reference: Nunez, F.J. et al. IDH-R132H acts as a tumor suppressor in gliomas via an epigenetic up-regulation of the DNA damage response. Translational medicine science (2019) DOI: 10.1126 / scitranslmed.aaq1427
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