- 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
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
The novel study was
reported in the journal Cancer Cell
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.
‘Scientists discover that blocking telomere protein TRF1 in glioblastoma tumors and glioblastoma stem cells can inhibit tumor progression.’
GBMs occur in
almost 15% of all primary brain tumors and in about 60-75% of all astrocytomas.
Nearly 3% of all childhood
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.
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.
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.
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
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.
- 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
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