The reason behind longer survival rates among certain patients having brain tumour has been explored by the researchers at the University of Michigan, Ann Arbor. The study resulted in finding new treatment strategy to combine radiation therapy with cancer drugs designed to block DNA repair.
“Every 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 a senior author of the paper.
Glioma patients are frequently found to have mutations in a gene called isocitrate dehydrogenase 1 (IDH1). These patients specifically showed to be typically younger and live longer than those having tumours with normal IDH1 gene. Tumours with mutated IDH1 were less aggressive and much better at repairing DNA than other gliomas.
The researchers focused on low-grade brain tumours that carried a mutant IDH1 gene which encodes for a protein known to help cells produce energy. These brain tumours also carried normally found mutations in genes called TP53 (a tumour suppressor gene) and ATRX (a DNA-protein complex remodelling gene).
The scientists used genetically engineered mice to grow brain cancer cells that possessed mutant IDH1 gene along with mutated TP53 and ATRX gene. These mice showed to live longer than the control mice which were programmed to have a normal IDH1 gene while still harbouring mutations in TP53 and ATRX genes.
The study discovered that the IDH1 mutation made the tumour cells less aggressive as the cells divided at a lower pace than the controls and were much less likely to trigger tumour growth when implanted into mouse brain..
The disease-causing mutation changed the activity of IDH1 which activated a cascade of chemical reactions that modified the cancer cells’ genes. This increased the manufacture of DNA repair proteins in the cells.They also found that the IDH1 mutation made the tumours resistant to ionizing radiation compared to the control tumours.
These results led the researchers 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 in vitro.
“Our results demonstrate that the metabolic changes caused by the IDH1 mutation reprograms brain cancer cells,” said Dr. Castro. “The results from this study could be a blueprint for extending, if not saving, the lives of many patients.”he added.
The study was published in the journal Science Translational Medicine.
“These findings have the potential to impact many younger glioma patients with low grade tumors by either ‘curing’ them or extending their lives,” said Jane Fountain, Ph.D., program director, NIH’s National Institute of Neurological Disorders and Stroke.
Dr. Castro’s team has started planning a Phase 1 clinical trial which will test the safety and efficacy of the combination therapy strategy outlined in this study.