March 11, 2019Low Grade Gliomas
According to a study published in Science Translational Medicine (13 February 2019) a preclinical study suggests a common form of brain cancer may be treated with combination radio- and chemotherapy. A study of mice and human brain tumors searched for new treatments by exploring the reasons why some patients with gliomas live remarkably longer than others. The results suggested that certain patients' tumor cells are less aggressive and much better at repairing DNA than others but are difficult to kill with radiation. The authors then showed that combining radiation therapy with cancer drugs designed to block DNA repair may be an effective treatment strategy.
The authors focused on low-grade gliomas that carry a disease-causing mutation 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 primary low-grade gliomas, a common and lethal form of brain tumor. Glioma patients whose tumors have mutations in IDH1 are typically younger and live longer than those whose tumors have 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).
For the study, the authors recreated the patients' tumors by genetically engineering mice to grow brain cancer cells that have the disease-causing mutations in IDH1, along with mutations in TP53 and ATRX. Like the patients, these mice lived longer than control mice whose tumors were programmed to have normal IDH1 while still harboring the mutations in TP53 and ATRX. When the authors examined the tumors, they found that the IDH1 mutation made the glioma cells less aggressive. The cells divided at a lower rate than the controls and were much less likely to trigger tumor growth when implanted into mouse brains. It was also discovered that the IDH1 mutation, in the presence of mutations in TP53 and ATRX, made the tumors resistant to ionizing radiation, a treatment that kills cells often by damaging DNA. For instance, radiation exposure extended the lives of mice that were implanted with control tumors but had no effect on mice implanted with IDH1 mutant cells.
Further experiments provided a possible explanation for this resistance. The results suggested the disease-causing mutation changed the activity of IDH1 which, in turn, triggered a cascade of chemical reactions that modified the cancer cells' genes in a way that increased the manufacture of proteins known to repair damaged DNA. According to the authors, the results demonstrate that the metabolic changes caused by the IDH1 mutation reprograms brain cancer cells.
These results then led the authors to formulate and test a new combination therapy. They found that they could extend the lives of mice with mutant IDH1 tumors by exposing them to radiation while also injecting them with anti-cancer drugs designed to block DNA repair. In contrast, treating these mice with either radiation or one of the drugs alone had no effect. Several of the findings seen in mice were also seen in human gliomas grown in vitro.
The authors have started planning a Phase 1 clinical trial which will test the safety and efficacy of the combination therapy strategy outlined in this study.