Effective Therapy Against Glioblastoma by Attacking Telomeres

Researchers have shown that it is possible to block the growth of human and murine glioblastoma in mouse models by blocking the TRF1 protein; an essential component of the telomere-protective complex.

The Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) has shown that it is possible to block the growth of human and murine glioblastoma in mouse models by blocking the TRF1 protein, an essential component of the telomere-protective complex known as shelterin. The study describes a new and promising way to combat this type of brain tumor, considered one of the most lethal and difficult to treat, by attacking its ability to regenerate and divide immortally.

The average life expectancy of patients with glioblastoma is about 14 months. This brain tumor (which is the most common) can evade and overcome the limited therapeutic options that exist today to treat it. It is particularly known for its ability to regenerate, because, the tumor contains a subset of cells with characteristics that are similar to stem cells, called glioblastoma stem cells (GSCs). One of these cells is capable of reproducing the entire tumor.

These GSCs cells are the cornerstone of glioblastoma and one of its identifying features. One of their characteristics is that they have very high levels of the telomeric protein TRF1, which in addition to being essential for protecting telomeres, is required to maintain the capacity of these cells to regenerate the tumor.

"We know that TRF1 is expressed particularly in stem cells, so we thought it would be interesting to see what would happen in tumors that had a strong tumor stem cell nature if we blocked TRF1," explains Maria A. Blasco (pictured left), head of the Telomeres and Telomerase Group and senior author of the paper. Glioblastoma is clearly a type of tumor that could benefit from blocking TRF1 owing to the ability of its glioma stem cells to regenerate the tumors after current treatments.

Blocking TRF1 reduces tumor growth

"The first thing we saw was that TRF1 is highly overexpressed in both mouse and human glioblastomas, which indicated that by blocking it we could perhaps impair its growth," says Leire Bejarano (pictured right), a member of Blasco's group and first author of the paper.

Consequently, Blasco, Bejarano, and colleagues started working with mouse models. They removed TRF1 during the initiation of the tumor, as well as blocked it once the glioblastomas had already formed. "Both strategies -- said Bejarano -- led to a significant increase in the survival rate of the mice with glioblastomas." In the first case, the increase in survival was of 80% and in the case of already-existing tumors the increase in survival was of 30%.

By studying the mechanisms by which TRF1 inhibition limited tumor growth, they found that inhibiting TRF1 caused a reduction in the proliferation and in the stem properties of glioma stem cells. This was in turn triggered by an increase in DNA damage at telomeres, which resulted from the destruction of glioblastoma telomeres. In the end, they prevented the tumor cells from continuing to multiply.

After the success in the mouse models, they began to work with human tumor cells. This required grafting glioblastoma stem cells derived from human patients into mice and treating them with a series of compounds developed at CNIO that inhibit TRF1 and which mechanism of action has been described recently by the same CNIO group. When compared with the animals treated with TRF1 inhibitors with those treated with a placebo, those treated with the TRF1 inhibitor displayed a reduction in the growth and size of the tumors, accompanied by an 80% decrease in tumor TRF1 levels and an increase in the survival rate.

A new therapeutic window

In addition to the anti-tumoral properties observed, blocking TRF1 appears to be safe because it did not affect the olfactory and neuromuscular functions, nor the memory, of the mice. This strengthens the idea that we now have a new therapeutic window to inhibit TRF1 in this type of brain tumor.

"It has a major therapeutic effect on glioblastoma," says Blasco. "We see that inhibiting TRF1 is an effective strategy for treating glioblastoma both by itself and in combination with current radiation and temozolomide therapies," explained the authors, who also collaborated with the Seve-Ballesteros Foundation Brain Tumor Group at CNIO, headed by Massimo Squatrito, the CNIO drug discovery Experimental Therapeutics Program, directed by Joaquin Pastor, and the CNIO Confocal Microscopy Unit, led by Diego Megías.

The next step -- which they are already working on -- is to verify the effectiveness of the TRF1 inhibitors developed at CNIO in combination with other drugs that are already being used in the clinic.

Illustration: Maria A. Blasco (left), senior author and Head of the Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO), and first author Leire Bejarano (right). CNIO.