Gliomas are the most common type of primary brain tumor. They can occur at any age and part of the brain or spinal cord where the glial cells—the support cells of the nervous system—are located. Current treatment for glioma includes a combination of radiotherapy and the chemotherapy agent temozolomide. Chemoresistance is one of the major causes of relapse as well as poor survival in patients. There are 40–50% of patients who are intrinsically resistant to temozolomide. However, a recent study carried out by the Spanish National Cancer Research Center (CNIO) and the Hong Kong University of Science and Technology (HKUST) shows that a subset of patients acquires a specific genetic alteration that can evade the combined therapy.

Their study, “MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas,” is published in Nature Communications and led by Massimo Squatrito, PhD, head of the Seve Ballesteros Foundation Brain Tumor Group at the CNIO, and Tao Jiang, MD, PhD, from Beijing Neurological Institute.

The researchers noted that temozolomide was becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. Like most chemotherapy drugs, temozolomide induces DNA damage in cancer cells. Gliomas can repair this damage through an enzyme encoded by the MGMT gene. In patients whose MGMT activity is blocked because of a modification of its promoter called “hypermethylation,” cancer cells cannot repair the temozolomide-induced damage and collapse.

“MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo,” wrote the researchers.

“Translocation of the MGMT gene was observed in a group of patients,” said Squatrito. “These genomic rearrangements involve the fusion of MGMT with other genes, which means that MGMT is now regulated by the promoters it is fused with, which contributes to its overexpression. When this type of rearrangements take place, the temozolomide-induced DNA damage is very efficiently repaired and the glioma continues growing even under treatment.”

Glioma cells (in blue) under temozolomide treatment, with DNA damage marked in brown. [CNIO]
To reveal the landscape of TMZ resistance in glioma patients, the team of researchers analyzed RNA-sequencing data of 252 TMZ-treated recurrent gliomas, among which 105 (42%) were newly collected. The team then integrated clinical information and performed bioinformatics analysis to determine the mutational status of several key alterations. Using the CRISPR-Cas9, the team at CNIO replicated some of these translocations in different cell and animal models and confirmed that they can confer resistance to temozolomide.
“It appears that the translocations are not present in the original tumor, only in recurrent ones, that are, tumors that emerge after the original cancer is treated,” Squatrito added. “This indicates that the resistance may occur as a consequence of the treatment itself.”

Their findings may lead to changes in the methods to monitor therapy efficacy: “Currently, the only known therapeutic biomarker in gliomas is the analysis of MGMT promoter status. When methylated, the MGMT gene is silenced and the patient is predicted to respond to temozolomide. The study showed this method is no longer valid when there has been a genetic translocation. The promoter might still be blocked, but the gene is being overactivated by other promoters and hence could contribute to tumor recurrence.”

The researchers also discovered that the MGMT translocations are present in exosomes. The researchers noted that if this finding is validated in patients, it can become helpful in detecting resistance early.

The researchers’ next goal will be to identify novel treatment intervention for the temozolomide resistant patients.

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