Reviewing What is Known of Alternative Lengthening of Telomeres

All cancerous cells must lengthen their telomeres in order to continue unfettered, harmful replication. Telomeres are repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, and cells with short telomeres following repeated replication become senescent or self-destruct. This is how the Hayflick limit on somatic cell replication is enforced. Unlike somatic cells, stem cells are privileged, and use telomerase to lengthen telomeres in order to produce daughter somatic cells via replication throughout life. Cancer cells, on the other hand, use either telomerase (~90% of cancers) or a partially explored set of mechanisms called alternative lengthening of telomeres (ALT, ~10% of cancers).

In this context, I'll mention what I think to be a good idea for a new biotech venture, suitable for someone who likes to take on a little more risk at the outset. Set forth to conduct a program of screening for small molecules that interfere in ALT. The aim is to discover compounds that can be used to treat the 10% of cancers that employ ALT, shutting down their ability to replicate. This is a somewhat open part of the field, as little funding goes towards such pure, focused discovery efforts in comparison to the funding for groups that already have an identified small molecule. Yet it is a reasonable wager that a large enough screening effort will turn up something useful along the way.

ALT is an attractive target for drug development. It only operates in cancerous cells, not normal cells, so there are fewer concerns regarding off-target effects. Interfering in ALT is a necessary part of a future universal cancer therapy that comprehensively prevents telomere lengthening. This is the best and most fundamental way to eliminate cancer, an approach that cancers can neither evade nor evolve resistance to. Even 10% of cancers is a vast market for one drug. The SENS Research Foundation tried a modestly sized screening program a few years ago, and didn't find good targets. Since then the research community has uncovered new information that might lead to a more guided screening process, such as the roles of FANCM and TRIM28. It is worth a try!

Alternative Lengthening of Telomeres and Mediated Telomere Synthesis

Telomeres are located at the end of eukaryotic chromosomes, and in humans, they are composed of TTAGGG tandem repeat DNA sequences and telomere-binding proteins. They are special structures that do not carry genetic information, and they comprise a proximal double-stranded region and the distal single-stranded region. Telomeres prevent the loss of genetic information during DNA replication and protect chromosomes from end fusion. Except in embryonic germ cells, stem cells, and cancer cells, telomere length gradually shortens with cell division. Short or dysfunctional telomeres are recognized as double-strand breaks (DSBs), triggering replicative senescence of cells.

Telomere maintenance is essential for genomic stability and survival of proliferating cells. To escape from the "Hayflick limit", the majority of tumor cells reactivate telomerase, which maintains telomere length. Telomerase maintains telomere length by adding telomere DNA repeats to the end of telomeres. This enzyme consists of a protein component with reverse transcriptase activity and an RNA component that is the template for telomeric DNA synthesis. However, approximately 10 to 15% of human tumors preferentially maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, which is a potential therapeutic target for telomerase-negative tumors.

The ALT phenotype has been observed in a broad range of human cancers, and some ALT-related cancers are aggressive. However, the development of anti-cancer therapeutics targeting the ALT pathway has been greatly limited by a failure to understand the molecular mechanisms underlying ALT pathway action and initiation. Here, we review recent discoveries regarding the ALT pathway mechanism and discuss possible cancer therapy targets in the ALT pathway.

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