An Investigation of How Telomerase Cancers can Switch to Become ALT Cancers

The paper I'll point out today is a timely one, given that the SENS Research Foundation's fundraiser for early stage work on a therapy for alternative lengthening of telomeres (ALT) cancers is nearing its close. There are still thousands of dollars left in the matching fund, so give it some thought if you haven't yet donated. The search for ways to safely sabotage ALT is a useful, important line of research because (1) blocking telomere lengthening is a path to a universal cancer therapy, (2) those research groups presently working on it are all looking to achieve this goal by interfering in the activities of telomerase, (3) cancers can switch from using telomerase to using ALT, and (4) next to no-one is working on ways to suppress ALT mechanisms. It seems fairly clear based on the evidence to date that the universal cancer therapy that lies ahead, built by inhibiting telomere lengthening, must involve a blockade of both telomerase and ALT. The open access paper below reinforces this point, the authors investigating how exactly cancers switch from telomerase to ALT to maintain their dangerous growth.

Cancer research today has a grand strategy problem. There is only so much funding and only so many researchers, but hundreds of subtypes of cancer. Therapies tend to be highly specific to the peculiarities of one type of cancer or a small class of cancers, meaning that great expense and time leads to a treatment that is only applicable for a fraction of cancer patients, all too often a tiny fraction. Further, since tumors evolve at great speed, any one individual patient's cancer may find its way out from under the hammer by changing its signature and mode of operation. All is not doom and gloom, however. Consider that the research community could build a therapy applicable to all cancers with little to no modification, where the cost of development would be no greater than any one of the highly specific therapies presently in use and under development. That therapy would be, of course, based on the blockade of telomere lengthening. The act of telomere lengthening is fundamental to all cancers, and without it tumors can neither grow nor sustain themselves: every cell loses a little of its telomeres with each division, and those with short telomeres self-destruct or become senescent. There is no expectation that any cancer would be able to evolve a way around a loss of telomere lengthening: these are core cellular mechanisms, not amenable to radical change or reinvention by simple mutational damage. The promise here is that the economics of cancer research and development could be entirely changed for the better, and that every cancer would become tractable, open to effective treatment.

The SENS Research Foundation cancer program staff propose to use an assay for ALT activity to assess the contents of the standard drug library for anti-ALT capabilities. The hope is that this will turn up potential candidates for further development, as well as shed more light on the most promising molecular mechanisms and targets to consider for the goal of shutting down ALT entirely, and further lend support for other groups to join in and help speed progress. In many ways ALT is a much easier target than telomerase. No normal adult cell uses ALT, so it is possible to take an indiscriminate, and therefore less costly approach to treatment without harming the patient. Telomerase is essential to stem cells, however, and so forms of targeting will be essential for that side of the future of cancer therapies. The paper linked here adds to the weight of evidence indicating that anti-ALT therapies are a necessary complement to the anti-telomerase therapies that are presently in the early stages of development.

Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX

Continuous telomere loss which derives from DNA replication, drives the fusion of chromosome ends, leads to cell cycle arrest and induces cell senescence. However, tumour cells can maintain telomere length and proliferation through telomerase reactivation or the alternative lengthening of telomeres (ALT) mechanism. It is reported that approximately 85-90% of cancer types are telomerase-positive, which use its RNA subunit (termed TR or TERC) as a template and its telomerase reverse transcriptase (TERT) to maintain chromosomal ends. Due to lack of telomerase activity in human somatic cells, telomerase is considered as a potential target of cancer therapy. However, this strategy would be ineffective in several human cancers, which are lack of detectable telomerase activity and utilize the ALT mechanism relying on recombination-mediated telomere elongation. Previous studies have shown that anti-telomerase therapy provoked a switch from telomerase activity to the ALT mechanism in mice. Furthermore, it has been shown that the ALT is an alternative mechanism for telomere maintenance during oncogenesis, which would ultimately decrease the effectiveness of anti-telomerase treatment. Therefore, identifying the mechanism of ALT induction and the telomerase-ALT switch is beneficial in resolving the bottlenecks of anti-telomerase therapy.

ALT-positive cells typically contain abnormally heterogeneous telomeres, ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal TTAGGG repeats (ECTRs). Despite understanding the hallmarks of ALT, the mechanism of ALT induction remains unknown. The study of ALT activation which transformed a telomerase-positive cell line into an ALT-positive cell line in vitro is rare. Recently, several factors have been shown to contribute to ALT formation. It has been reported that the depletion of a histone chaperon ASF1 resulted in ALT cells induction and long telomeres elongation concomitant with inhibition of telomerase activity. Since the ALT mechanism is a recombination-mediated lengthening mechanism, the clustering of telomeres caused by DNA damage response (DDR) promotes homology-directed telomere synthesis, suggesting that DDR may play an important role in ALT induction. Further, somatic mutations of the histone variant H3.3, alpha-thalassemia X-linked syndrome protein (ATRX) and death associated protein (DAXX) have been found in ALT cancers. They are chromatin remodeling factors at telomeres, which are responsible for ALT activity. Furthermore, it has been shown that ATRX inhibits ALT and relates to telomerase assembly and depositing. Although single and double deletion of ATRX and DAXX could not initiate the ALT mechanism, histone management dysfunction and chromatin structure disorder might provide a suitable genomic environment for ALT induction. Lastly, telomerase activity plays very important role in ALT repression. Inhibition of telomerase activity might promote ALT induction. It has been shown that genetic extinction of telomerase in T cells of ATM knockout mice results in tumor emergence, concomitant with the increase of APB and C-circles.

To determine the mechanism by which telomerase-positive cancer cells switch to ALT and to elucidate the mechanism of ALT induction, we induced telomere-specific DNA damage, disrupted the function of the ATRX/DAXX complex and inhibited telomerase activity in telomerase positive cancer cells, which successfully transformed a telomerase-positive cell line into a ALT-positive cell line.

Comments

I think the part that I struggle with, is why is SENS pouring any of its limited resources into cancer research at all? It's not that curing cancer isn't important, but it already gets billions in research funding every year from other groups and there are a lot of promising therapies in development that have been mentioned here on this blog, such as re-engineered immune cells, that might make this research unnecessary.

I wonder if perhaps others feel this way and this is why the SENS ALT cancer project isn't receiving the interest that other crowd sourced anti-aging projects have.

Posted by: Link at September 3rd, 2016 12:33 AM

@Link the problem is ALT cancer is NOT well funded only regular cancers (telomerase based ones) are really getting the funding. This idea that all cancer research is well funded is exactly why SENS is doing this. Please if anyone here has not donated and are sitting on the fence just remember that ALT cancer is not well funded, it isnt fully understood and it is highly important for longevity.

Posted by: Steve Hill at September 3rd, 2016 4:30 AM

@Link: I suspect that is not an uncommon viewpoint, and this project has certainly been tougher to raise for than others in recent years.

But consider that one could argue in exactly the same way that aging research as a whole gets billions in funding every year, so why fund any of SENS? The point is that the large-scale funding in these communities isn't going to the right destinations to create radical leaps forward in medical capabilities - at a time when those radical leaps forward are possible and plausible. All of SENS is an attempt to bootstrap the viable, high-expectation lines of research that are not getting the attention merited by the results they can create.

Posted by: Reason at September 3rd, 2016 6:58 AM

i agree that blocking the lenthening of telomeres is the most promising direction in cancer research. I just wonder why there is so little focus on the ALT-mechanism in the field? Without stopping ALT, controlling telomerase-based lenthening seems next to useless, given the ability of switch under selective pressure. I just wonder if one day (hopefully soon) we succed in blocking lenthening of telomeres, would this really mean that cancer, every form of it, is dead?

Also, how do we make sure that stem cells can still lengthen their telomeres?

Anyway, I will make a little donation to your project.

Posted by: K. at September 3rd, 2016 10:41 AM

@K.: The focus on telomerase and not on ALT may be driven by the fact that telomerase was already long the subject of research for many other reasons, while ALT just doesn't happen in the normal adult body. So sufficient knowledge of ALT to go somewhere with it didn't exist until comparatively recently.

The use of telomere lengthening blocking therapies will have to either be transient - in that the patient can endure a lack of telomerase in stem cells for longer than the cancer can survive without it - or targeted to cancer cells in some way. Targeting is a very active area of development, with many different approaches, but that does tend to push things back to a cost for adapting to each type of cancer. Global interdiction of telomere lengthening seems plausible, but again it all depends on how long it would take to wait out the cancer. Perhaps it could be coupled with the introduction of new stem cells in vulnerable populations.

Donations are always appreciated, thank you!

Posted by: Reason at September 3rd, 2016 11:09 AM

Thanks for the explanation.

When stem cells are deprived of telomerase, their telomeres will shorten which might induce enhanced genomic instability as these 2 things (telomere length and genomic stability) have been linked in some studies. So basically we have to know how short can the telomeres of the stem cells become without being susceptible to genomic instability (or be sure in the first place that this is really a fact). But generally speaking, as cancer cells divide much faster than stem cells, they ought to use their telomeres much quicker. Is that right?

In the long run, I hope it will be possible to reprogram stem cells and modulate their microenvironment so that they can be set back to a youthful state. This would be a big breakthrough.

I'm just getting started here. I will support your projects in the future as well and be inolved in aging research myself. Good luck and i look forward to the future. ;)

Posted by: K. at September 3rd, 2016 12:23 PM

It is plausible to target cancerous cells only with a telomerase inhibitor and leave the healthy cells alone. A surface marker or other way to isolate the cancer cells would be needed but its possible and far better than system wide telomerase inhibiting in my view. Thankfully a number of groups are working on telomerase therapies so we should get something workable from someone.

Thank you also for donating to the campaign it really is very important we get a handle on ALT.

Posted by: Steve Hill at September 3rd, 2016 4:12 PM

I have donated $350, but that was before the matching. Then I donated $10 as asked for in the mail. If everybody had done that. The important thing here is to get more donors into lifespan.io. so that not the same have to contribute with much of their funds.

Posted by: Extra Life at September 3rd, 2016 4:28 PM

@Extra Life : Agreed. I also donated more than usually before the matching fund was announced. I'll give again before the campaign ends.

Posted by: Spede at September 3rd, 2016 5:12 PM

It might not be the case that an ALT targeting therapy is used alongside a telomerase blocker to kill all cancer cells, but just to slow the cancer cells down for a while as other therapies do the killing. Much like barb wire slow enemy soldiers so that a machine gun can better kill them...

Posted by: Jim at September 3rd, 2016 8:51 PM

@Spede: I will also donate more if I see that the match is not matched. I'm new donor and new into this and will follow up and donate to SRF in October. And I will donate for all the 3 previous SRF October when I weren't reading FA! I have made a "rule" for my self: I see it that way and note in a document how much I have donated to various projects and give myself points. I give double points when I donate to a match fund that matches 1:1. I not I have collected $1 for every $ donated. Everyone should do that and it make it more fun and if everyone does that the match would be reach as it were written in the mail: If everyone donates $10.

Posted by: Extra Life at September 4th, 2016 5:32 AM

I give myself points much as in a video game. And I hope that in the future with these therapies I can buy myself an extra life!

Posted by: Extra Life at September 4th, 2016 5:34 AM

Would it be possible to first block the lengthening of telomeres in cancer cells and then, after the cancer cells died, to apply telomere lenghtening therapies to undo possible damage in healthy cells?

Posted by: Claus at September 6th, 2016 4:24 AM

@Extra Life : Thank you, be sure to look at how the campaign is going during its very last days. It would be unfortunate that you miss the deadling for donations.

Money's a bit tight for me, but at try to give at least once a year ; and of course more than that when there are SENS-related crowdfunding campaigns.

I like your idea of making it like a game - and the analogy of the extra life is very fitting !

Posted by: Spede at September 6th, 2016 5:35 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.