A Potential Approach to Sabotage Telomerase in Cancer Cells

Advocates for cancer research often bemoan the enormous complexity of cancer, the vast range of differences between types of cancer and even between cancers of the same type in different individuals. A cancer is cellular evolution on fast forward, rampant growth and mutational damage, which has made it a thousand moving targets for the research community. However there is a commonality to all cancer, and that is the need for cancer cells to maintain lengthy telomeres through the use of telomerase or less well understood alternative lengthening of telomeres (ALT) methods. Without this abuse of telomere lengthening mechanisms cancerous cells would not be able to continuous replicate to a degree that makes their presence life-threatening. A little of the length of telomeres are dropped every time a cell divides, and when they become too short the cell permanently ceases replication and usually activates its own programmed cell death process. This insight is the basis for the SENS approach to cancer, which is to aim at suppressing all mechanisms by which the body can lengthen telomeres.

What other approaches might be taken to attack this potential single point of failure in all cancers? These researchers are attempting to corrupt the process of telomere lengthening via telomerase in cancer cells so as to generate telomere sections that a cell considers to be damaged. This then results in much the same outcome as for very short telomeres, which is to say no more replication for the affected cells:

[Researchers] have targeted telomeres with a small molecule called 6-thio-2'-deoxyguanosine (6-thiodG) that takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumor growth. 6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell can no longer divide and dies though a process known as apoptosis.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies. Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials, researchers noted. "Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point." Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG. "We observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage in mice."

Link: http://www.eurekalert.org/pub_releases/2015-01/usmc-rtt123114.php

Comments

Doesn't this have the same problem as other forms of WILT?
We will need to replace their stem cells if this kills all telomerase-using cells.

Posted by: Carl at January 1st, 2015 10:06 PM

Being able to selectively destroy telomerase expressing cells would be an improvement over WILT. With WILT, because no cells have telomerase it is necessary to regularly replace stem cells to avoid the complete failure of tissue maintenance. However, with this sort of idea, it would only be necessary to supply replacement (telomerase negative) stem cells for the duration of cancer treatment (and once the cancer has been destroyed, normal stem cells can be given). The rest of the time a person can have telomerase positive cells with no need for regular stem cell replacements. The other issue is degree of difficulty. It is very hard to safely add or delete genes in every cell in a living organism; it is much easier to do that in cells cultured outside the body.

Posted by: Arcanyn at January 2nd, 2015 3:23 AM

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