An Approach to Disabling Telomeres in Cancer

The present swamp of slow and expensive progress in cancer research is a swamp because every type of cancer is biologically very different, and most research programs are thus applicably only to a narrow slice of the exceedingly broad spectrum of cancers. Even there it is frequently the case that individual tumors are so highly varied that a vulnerability in one individual's cancer of a specific type is not present in another. There are better ways forward, however: progress in cancer research can be greatly accelerated by finding and focusing on common mechanisms shared by many different cancers. This has long been the SENS approach to cancer, to strike at the one known common mechanism shared by all cancers, which is to say their need to extend telomeres. Telomeres shorten with each cell division, and when too short a cell will destroy itself. This limits the number of times any ordinary cell in the body can divide, and cancers must thus break this limiting function in order to retain their uncontrolled growth.

A decade ago it was sadly the case that, as for any bold new plan, the SENS research program as an approach to medicine to treat degenerative aging and its consequences - such as cancer - was mocked. Today, however, numerous research groups are attempting to disrupt telomere extension in cancer. Times have changed, and the world is finally catching up to the perspective of earlier visionaries in aging research. Present work on disruption of telomere lengthening in the broader scientific community is largely aimed at blocking the activity of telomerase, while the SENS Research Foundation cancer program nowadays focuses on the less well researched alternative lengthening of telomere mechanisms.

Here researchers are taking an entirely different approach by attacking the structure of telomeres directly, rather than interfering in lengthening mechanisms, thus stripping telomeres from chromosomes in target cells:

Researchers 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: by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer. "Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer."

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, 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.

Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times - this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin, which forms a protective covering. The research 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 in both healthy and tumour cells.

"Nobody had explored the idea of using one of the shelterins as an anti-cancer target. It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense. TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects." 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. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development."



This is probably one of the most significant Cancer studies of recent time and from one of the leading experts in Telomere biology. I suspect the CNIO may well achieve ONCOSENS before SENS the rate of progress Maria Blasco is making in various directions.

She has also I hear joined forced with Dr Fossel to work on Telomerase gene therapy and are applying for new drug testing and FDA clinical trials in people. I suspect this may be very soon given they have the funding to do this already.

Posted by: Steve H at May 19th, 2015 2:09 AM

Yes, it's a very important study. Maria and I have been interacting on these issues for many years - it's no accident that she is on our Research Advisory Board. I know she will recognise that the toxic effects may prove to be less "bearable" than they so far seem, though. That's why it still makes sense to press on with a range of approaches.

Posted by: Aubrey de Grey at May 20th, 2015 7:47 AM
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