Novel Targeted Therapy Against Glioblastoma

Researchers at the Spanish National Cancer Research Centre used mouse models to suppress glioblastoma tumor growth by blocking TRF1 telomere protein.

Highlights:

Scientists at the Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) used mouse models to suppress glioblastoma tumor growth by blocking TRF1 telomere protein
The scientists discovered that overexpressed TRF1 in mouse and human glioblastomas could be inhibited in mouse and human models.
They discovered that blocking TRF1 suppressed the tumors by 80% and increased the survival rates.

Scientists at the Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) used mouse models to suppress glioblastoma tumor growth by blocking TRF1 telomere protein.

The novel study was reported in the journal Cancer Cell

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Glioblastomas are tumors that arise from astrocytes that make up the supportive tissue of the brain. Glioblastomas are usually highly malignant.

‘Scientists discover that blocking telomere protein TRF1 in glioblastoma tumors and glioblastoma stem cells can inhibit tumor progression.’

What is Glioblastoma?

Glioblastomas (GBM) are dangerous brain tumors originating in astrocytes (star-shaped cells) which make up the supportive tissue in the brain. These are malignant and spread rapidly, thus making it difficult to treat. GBMs can occur anywhere in the brain as well as in the spinal cord.

GBMs occur in almost 15% of all primary brain tumors and in about 60-75% of all astrocytomas. Nearly 3% of all childhood brain tumors are GBMs. The exact cause of these tumors is unknown.

The most common symptoms of GBMs include severe headache, nausea, vomiting, drowsiness, confusion, memory loss, weakening limbs, slurring speech and visual disturbances.

GBMs are difficult to treat because these tumors are comprised of different types of cells, including a subset of cells called glioblastoma stem cells (GSCs) that are similar in characteristics as stem cells. They can thus regenerate. A combined approach is usually used to treat GBMs which may include surgery, radiotherapy and chemotherapy. Most GBM affected patients have a survival period of 12-14 months.

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Novel Targeted Therapy against Glioblastoma

A single glioblastoma stem cell (GSC) has the capability to produce an entire tumor and hence is one of the identifying features of glioblastoma. GBM tumors and GSC cells have high levels of telomere protein TRF1 which causes aggressive growth of tumors. DNA damage of telomere genes occurs due to mutations. According to Dr. Maria A. Blasco, Head of the Telomeres and Telomerase Group and senior author of the paper, says that it was already known that TRF1 is overexpressed in GSCs and the group thought it would be interesting to see if blocking TRF1 could suppress the tumors. TRF1 is the clincher in the proliferation of adult and pluripotent stem cells.

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Blocking Telomere Protein TRF1 Acted as a Tumor Suppressor

Blasco’s group first worked with mouse models to block TRF1 in initial tumors as well as existing tumors. Leire Bejarano, first author of the paper said that this strategic blocking of TRF1 inhibited the proliferation of both adult and stem cells in GBM. The tumor cells were prevented from further multiplying thereby increasing the survival rate of the mice with both GSC and existing tumors.

The scientists then carried out a xenograft of human glioblastoma stem cells from patients into mice and then treated them with compounds developed at CNIO to inhibit expression of TRF1. The mice treated with TRF1 inhibitor exhibited a decrease in the size of tumors along with 80% decrease in tumor TRF1 levels and better survival rates. The study found that targeting telomeres through TRF1 inhibition effectively controls GBM growth.

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Therapeutic Applications

TRF1 inhibition in GBMs and GSCs appears to be a safe therapeutic option. This mode of treatment did not have significant side effects like neuromuscular damage, memory damage, vision or hearing loss. This research has immense therapeutic potential for treating GBMs along with existing treatment modes like radiotherapies and temozolomide, an oral chemotherapeutic drug.

The next step for the group in developing this as a mainstream therapeutic option is to ascertain the effectiveness of the TRF1 inhibitors developed at CNIO with other combination therapies already in use.

If the group is able to verify these TRF1 inhibitors and develop a safe therapy, it could be a game changer in GBM treatment and significantly improve the poor prognosis of GBM.

References:

Leire Bejarano, Alberto J. Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito and Maria A. Blasco. (2017). “Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts”, Cancer Cell 32(5), pp.590-607. DOI: http://dx.doi.org/10.1016/j.ccell.2017.10.006
Brain Tumor - (http://www.abta.org)

Source-Medindia