Researchers have found that a genetic mutation, seen in about half of all brain tumours produces a response that prevents radiation treatment from working.

Altering that response using FDA-approved drugs restores the tumour's sensitivity to radiation therapy and extends survival in mice.

The paper, which represents more than five years of research has been published in the journal Science Translational Medicine.

"These findings have great potential to impact medical treatment of patients with low-grade glioma, which is critically needed for this terrible disease," says senior author Maria G. Castro, Ph.D., R. C. Schneider Collegiate Professor of Neurosurgery and a professor of cell and developmental biology at Michigan Medicine.

The IDH1 gene is mutated in about half of gliomas - which is the most common type of brain cancer.

These tumours tend to be low-grade and occur at a younger age, with survival rates ranging from seven to ten years.

"The challenge is that following initial treatment with surgery and chemotherapy, the tumours always come back and they come back with a vengeance," Castro stated. "If we can intervene early in this diagnosis, before the tumour comes back more aggressive and deadly, it could have a big impact for these patients."

The researchers created a mouse model of IDH1-mutant glioma.

The IDH1 mutation does not in itself cause cancer.

For a tumour to form, mutations must occur in IDH1, p53 and ATRX.

The researchers discovered that when all three mutations are present, mutated IDH1 increases the tumour cells' DNA damage response.

This reduces the efficacy of the radiation treatment, as the cancer cells can now correct the radiation-induced DNA damage.

Adding a drug that inhibits a critical pathway in DNA damage repair made the tumours sensitive to radiation treatment.

Researchers initially discovered this using the newly created mutant IDH1 mouse models and confirmed their findings in tissue samples from patients with IDH1-mutant glioma.

This suggests that a precision medicine approach to gliomas would better direct their treatment.

"Our findings elucidate how mutant IDH1 interferes with current glioma treatments and provides a blueprint on how to overcome such interference. As a direct consequence of these data, we will implement a series of novel clinical trials at our institution in the near future," said Pedro R. Lowenstein, M.D., Ph.D., Richard C. Schneider Collegiate Professor of Neurosurgery and professor of cell and developmental biology.

The FDA has already approved DNA repair blockers to enhance sensitivity to chemotherapy or radiation in some cancers.

The researchers are currently working with colleagues in radiation oncology, pathology, neuro-oncology and neurosurgery to translate their findings into a clinical trial to test the combination in patients with low-grade gliomas with IDH1 mutation.

Pathologists already test for IDH1 mutation as part of the diagnostic process because it influences prognosis and treatment, so this therapeutic strategy would be straightforward to implement in the clinic.

"Now we have a potential new way of treating these tumours, that will make radiation deliver a much bigger impact," says lead study author Felipe J. Nunez, Ph.D., a research specialist in the Castro/Lowenstein lab. "By combining these two approaches, we hope that the new treatment will extend remission in these patients and potentially turn low-grade glioma into a chronic disease."

Source: Michigan Medicine - University of Michigan