By inhibiting a protein called telomeric repeat binding factor 1 (TRF1), researchers were able to stop the growth and division of murine and human glioblastomas.
Senior study author Maria A. Blasco, head of the Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) in Madrid, Spain, and colleagues recently reported their findings in the journal Cancer Cell.
According to the American Brain Tumor Association, glioblastoma accounts for around 15.4 percent of all primary brain tumors in the United States.
Fast-growing and difficult to treat, glioblastoma is one of the deadliest brain tumors. It is estimated that for people with aggressive glioblastoma who are treated with a combination of temozolomide — a chemotherapy drug — and radiation therapy, the median survival is just 14.6 months.
Blocking TRF1 reduced glioblastoma growth
Glioblastomas develop from star-shaped brain cells called astrocytes. These tumors also contain a subset of cells called glioblastoma stem cells (GSCs), which enable the tumors to regenerate. This is one reason why glioblastoma is so difficult to treat.
The researchers note that stem cells contain high levels of the TRF1 protein. TRF1 is a component of shelterin, which is a protein complex that helps to safeguard telomeres — that is, the protective caps at the end of chromosomes.
Additionally, TRF1 plays a significant role in the tumor-regenerating abilities of GSCs. With this in mind, Blasco and her colleagues sought to determine how blocking TRF1 might influence glioblastoma growth.
The researchers removed TRF1 during the formation of glioblastoma tumors in mouse models. This reduced glioblastoma growth in the rodents and increased their survival by 80 percent.
When the team blocked TRF1 in glioblastomas that had already formed in the mice, the rodents' survival rose by 30 percent.
On further investigation, the researchers found that blocking the TRF1 protein in glioblastoma tumors caused damage to the DNA of telomeres in GSCs, which prevented these cells from proliferating.
'A major therapeutic effect on glioblastoma'
Next, the team moved its experiments to human glioblastoma cells. This involved removing GSCs from glioblastoma tumors in people with the brain cancer, before transplanting them into rodents.
The researchers then treated the rodents with compounds developed at CNIO that block TRF1, and their outcomes were compared with mice that were treated with a placebo.
The team found that the mice that received the TRF1 inhibitors not only showed an 80 percent reduction in tumor TRF1 levels, but they also experienced a decrease in the growth and size of glioblastoma tumors and increased survival when compared with mice that received a placebo.
The researchers note that inhibiting TRF1 appeared to have no adverse effects in the rodents.
Overall, Blasco and team believe that their study points to TRF1 inhibition as a potential treatment for one of the deadliest brain cancers.
"It has a major therapeutic effect on glioblastoma. We see that inhibiting TRF1 is an effective strategy for treating glioblastoma both by itself and in combination with current radiation and temozolomide therapies."
Maria A. Blasco
The researchers now plan to assess the efficacy of TRF1 inhibitors in combination with other drugs already used in the treatment of glioblastoma.