Researchers have successfully ‘uncapped’ telomeres in animal lung cancer model.

Scientists from the Spanish National Cancer Research Centre (CNIO) have discovered a new strategy to fight cancer, which is very different from those described to date. Their work shows for the first time that telomeres, the structures protecting the ends of the chromosomes, may represent an effective anti-cancer target.  The team state that by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer.  They go on to add that telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer.  The opensource study is published in the journal EMBO Molecular Medicine.

The researchers explain that every time a cell divides, it must duplicate its genetic material, the DNA, which is packed inside the chromosomes. However, given how the mechanism of DNA replication works, the end of each chromosome cannot be replicated completely, and, as a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells, which stop replicating, and eventually, the cells are eliminated by senescence or apoptosis.

This phenomenon has been known for decades through previous studies, as well as the fact that it usually does not occur in tumour cells. Cancer cells proliferate without any apparent limits, and therefore, they are constantly dividing, but their telomeres do not gradually become shorter; the key behind this mechanism is that the telomerase enzyme in cancer cells remains active, while in most healthy cells telomerase is turned off. The constant repair of telomeres by telomerase is, in fact, one of the mechanisms that allows tumour cells to be immortal and divide endlessly.

Hence, an obvious strategy to fight cancer is to inhibit the telomerase enzyme in tumour cells. This approach has been tested before in past studies, but with worrisome results; telomeres do shorten, but this shortening is lethal to tumour cells only after a variable number of cell divisions necessary for telomeres to become completely eroded, thus the effects are not instantly seen.

In the current study the researchers also target telomeres, but their approach is completely different from past telomerase-inhibition theories.

Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times, explain the team, this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin (from the term shelter or protection), which forms a protective covering. The team strategy consisted of blocking one of the shelterins, namely TRF1, so that that the telomere shield was destroyed.  The idea of targeting one of the shelterins has not been tried so far, due to the fear of encountering many toxic effects caused by acting on these proteins that are present

The current study shows that blocking TRF1 only causes minor toxicities that are well tolerated by mice.  It does however prevent the growth of lung carcinomas already developed in mice.  The data findings showed that TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. This strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects.

TRF1 has been inhibited both genetically, in mice where the gene has been removed, and chemically using selected compounds from CNIO’s proprietary collection of active compounds. These compounds, including the inhibitor ETP-470037 developed by the CNIO Experimental Therapeutics Programme, may provide a starting point for the development of new drugs for cancer therapy.

The researchers worked with mouse models for lung cancer, the cancer type that has the highest death rates worldwide. Specifically, they used a mouse with a very aggressive type of lung cancer for which no drug targets have been found to date.  The tumours have an active K-Ras oncogene and the p53 tumor suppressor is missing. TRF1 is the first target that is able to inhibit the growth of these highly aggressive tumours.

The next aim was to demonstrate that TRF1 is really an anti-cancer target. To do so, the researchers genetically blocked its activity in mice with lung cancer as well as in healthy mice, in order to test the toxicity of the procedure.

Having established the effectiveness and low toxicity of the new target, the researchers searched for chemical compounds that could have activity against TRF1. Two types of compounds have been found with the team now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development.

Source:  Centro Nacional de Investigaciones Oncológicas (CNIO)

Lung cancer cells treated with the CNIO TRF1 inhibitor ETP-47037 (right) show less TRF1 bound to the telomeres (green, top), more telomeric DNA damage (pink, bottom), and therefore, an acute telomere uncapping, than non-treated cancer cells (left).  Credit:  CNIO.
Lung cancer cells treated with the CNIO TRF1 inhibitor ETP-47037 (right) show less TRF1 bound to the telomeres (green, top), more telomeric DNA damage (pink, bottom), and therefore, an acute telomere uncapping, than non-treated cancer cells (left). Credit: CNIO.






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