December 19, 2017 Cancer and telomeres

A group of Spanish researchers from the National Cancer Research Centre (CNIO) discovered a novel and promising strategy able to limit the growth of glioblastoma, one of the most aggressive and with worst prognosis types of cancer.

The work has been recently published in the Cancer Cell journal

Glioblastoma is a type of cerebral cancer with a very low life expectancy that ranges between 12 to 15 months. The aggressiveness comes from the presence of cells with properties similar to “stem cells” (Cancer Stem Cells), which confer high proliferation capacity and radio and chemoresistance to the tumour.

Their work looks at telomeres, which are regions of DNA at the ends of each chromosome. The telomeres are further protected by a protein shield called Shelterin complex. The maintenance of telomeres is a key process to safeguard the genetic information in cells and it is critical to maintain the proliferation capacity of tumour cells. What CNIO researchers observed was that TRF1 protein, an important factor for the stabilization of the Shelterin complex, is particularly abundant in stem cells from glioblastomas (CSC).

Given the importance of TRF1 in telomere maintenance in cancer cells, the researchers aimed to develop a novel therapy based on the destabilization of telomeres by inhibiting TRF1. First, using mouse models, they observed that the deletion of TRF1 gene promoted a significant decrease in glioblastoma tumour growth. Accordingly, TRF1 deletion leads to mice living 5 times longer, when compared to wild-type animals. Looking closer to the mechanism behind this improvement what they showed is that the deletion of TRF1 increases the load of DNA damage in the telomeric regions that results in lower proliferation capacity and loss of stem cell properties.

Since targeting TRF1 reduced mice tumours, the authors treated human tumours engrafted in mice with a inhibitors of TRF1. They observed a significant reduction in tumour size and also an increased lifespan of treated animals. Initial toxicology in mice is encouraging as active TRF1 inhibitors had no side effects; the vital functions of mice such as neuromuscular, olfactory or memory functions were not compromised. Although still a long way to the clinic, the therapeutic potential of TRF1 is certainly worth to explore further including their effect in combination with other strategies already in the clinic such as radiotherapy or chemotherapy to determine whether there is a synergistic effect.

 Telomeres have been explored for many years as drug-targets in oncology. This study on the destabilization of telomeres may represent a new avenue for an effective therapy against glioblastoma and perhaps to other types of cancer. Validated telomere testing technologies are required to monitor the efficacy of these compounds and should be included as companion biomarkers.

These findings offer new insights towards cancer treatment where telomeres not only could be used as biomarkers but they represent a key target in the fight against it.

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