Control ALT, Delete Cancer: Why is this important?

A new crowdfunding campaign at lifespan.io by Dr. Haroldo Silva and the SENS Foundation is focusing on destroying cancer cells’ ability to divide indefinitely. But what actually is ALT, and why is it so important? 

Cancers are extremely varied, but one thing they have in common is the ability to divide indefinitely, without experiencing something called replicative exhaustion. Your average cell can only divide a certain number of times before its telomeres reach critical length – pushing it into either apoptosis or senescence. While certain cell types like stem and germ cells have privileges when it comes to this, in order for cancer to survive it has to find ways to divide far more than it normally could. 

There are 2 known ways cells can extend telomeres

The easiest way for cancer to do this is simply to reactivate the enzyme telomerase, which lengthens and repairs telomeres. This is called a telomere maintenance mechanism, TMM, and essentially adds new DNA to the end of the chromosome – this repairing the strand. The majority of cancer types use this mechanism to survive, and research is already targeting the TMM mechanism in the fight against cancer. 

Cancer is sneaky

We already have solutions when it comes to this mechanism, but there’s another, less studied mechanism cancer cells can also use called ALT (alternative lengthening of telomeres). These are often some of the trickiest cancer types to treat, and we currently have no drugs targeting the ALT pathway. Around 10% of cancers are currently estimated to use the ALT pathway. 

“There are about 1.4 million new cases and 820,000 deaths globally due to ALT cancers every year”

Credit: SENS Foundation. Detail redrawn from Figure 1: Structure of Telomeres,  pg. 320, Nature Reviews, Volume 11, May 2010, Alternative lengthening of telomeres: models, mechanisms and implications, Anthony J. Cesare and Roger R. Reddel

While conventional telomere extension involving telomerase is found in healthy cells across the body such as stem cells, ALT is not present in normal cells. This makes it specific to cancer cells, and therefore an excellent target. Furthermore, cancer can often become resistant to and overcome any telomerase based treatments, precisely by adopting the ALT strategy. 

Understanding ALT

Telomeres are made up of a repetitive DNA sequence wound around a group of proteins called the shelterin complex. Telomerase usually adds to this strand by essentially copying from its own RNA sequence. In cells that use ALT, some of these repetitive telomeric repeats appear to be detached from the chromosomes – perhaps acting as another form of template. There is also some suggestion that the cell might even use a sister chromatid’s telomeric DNA as a template for another. At this point the mechanism isn’t well understood, but we know ALT often begins with a loss of chromatin remodelling proteins at the telomeres; allowing a DNA damage response, recombination and abnormal protein behaviour to initiate ALT. 

An old pathway

Curiously, the ALT pathway may actually be the initial default method of telomere extension. It appears to have been evolutionarily conserved from yeast to humans, perhaps as an early way of protecting linear DNA when it transitioned from a more stable circular form. In fact, the ALT pathway is known to be used in embryonic development too, assisting with reprogramming. 

Developing therapies

In 2009, something called the telomeric C-circle was discovered – making it the first known specific ALT marker. This C-circle is a strand of circular telomeric DNA, and appears to be a good marker of ALT activity levels. An assay for markers like the C-circle could therefore be used for cancer screening in patients, and helps identify the presence of the ALT pathway. 

What about therapies? Well this is where the new SENS campaign comes in. ALT isn’t instigated by one specific enzyme which makes it harder to target. The new CTRL ALT Delete cancer campaign therefore aims to screen around 115,000 diverse compounds, to find those that inhibit this ALT pathway. Finding these compounds is a great start, from which we can build and design ALT targeting drugs. 

This is an important project, as cancer is one of the major threats to longevity. We need to develop ways to inhibit and block ALT, and you can help that happen! Check out the crowdfunding campaign here.

Want to find out more? Watch a video about the project below: