Progress Towards Blocking Alternative Lengthening of Telomeres in Cancer

Well, this is promising news. Researchers have found that inhibition of FANCM activity is a potential point of intervention to shut down alternative lengthening of telomeres (ALT) in cancer. This goal is one half of the ultimate cancer therapy, a form of treatment that is (a) capable of shutting down all forms of cancer, without exception, where (b) cancers cannot evolve resistance to its mechanisms, and (c) it requires little to no expensive, time-consuming adaptation for delivery to different cancer types. The other half is a method of blocking the ability of telomerase to lengthen telomeres, and several research groups have made inroads towards that goal. Both are needed in combination, since ALT cancers might evolve to become telomerase cancers, and vice versa.

Why would this work? All cancers absolutely require some method of lengthening telomeres in order to support their rampant growth, and - so far as we know - this means either telomerase or ALT. Telomeres are caps of repeated DNA sequences at the end of chromosomes, and a little of their length is lost with each cell division. They are a part of the counting mechanism that enables the Hayflick limit on cell division; when telomeres become short, a cell ceases to replicate and self-destructs. Only with continued lengthening of telomeres can a cell keep on dividing indefinitely. Without this, a cancer would wither away.

You might recall that the SENS Research Foundation team made an attempt to find ALT-blocking small molecules a couple of years ago as a part of the OncoSENS research program, supported by philanthropic crowdfunding. Unfortunately that failed, as small molecule screens sometimes do. It is a roll of the dice, consulting the vast compound databases in ways that are intended to maximize the odds. With the new results here, now perhaps work on the ALT side of the ultimate cancer therapy has a chance to forge ahead once more. A very positive development, for all of our personal futures.

New study reveals an unexpected survival mechanism of a subset of cancer cells

Embedded at the end of chromosomes are structures called "telomeres" that in normal cells become shorter as cells divide. As the shortening progresses it triggers cell proliferation arrest or death. Cancer cells adopt different strategies to overcome this control mechanism that keeps track of the number of times that a cell has divided. One of these strategies is the alternative lengthening of telomeres (ALT) pathway, which guarantees unlimited proliferation capability. Now, a research group has discovered that a human enzyme named FANCM (Fanconi anemia, complementation group M) is absolutely required for the survival of ALT tumor cells.

Previous studies have shown that a sustained physiological telomere damage must be maintained in these cells to promote telomere elongation. This scenario implies that telomeric damage levels be maintained within a specific threshold that is high enough to trigger telomere elongation, yet not too high to induce cell death. "What we have found is that ALT cells require the activity of the FANCM in order to prevent telomere instability and consequent cell death. When we remove FANCM from ALT tumor cells, telomeres become heavily damaged and cells stop dividing and die very quickly. This is not observed in tumor cells that express telomerase activity or in healthy cells, meaning that is a specific feature of ALT tumor cells."

FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.


>since ALT cancers might evolve to become telomerase cancers, and vice versa.

Is there a documented case where an ALT cancer switched to telomerase? I would guess that ALT would imply that there were already a lot of mutations and change to the cell machinery

Posted by: Cuberat at June 5th, 2019 6:31 PM

Very good!!

Posted by: Antonio at June 6th, 2019 6:45 AM

@Cuberat: I do not know, but it is certainly within the bounds of the possible. It doesn't seem any larger a leap than other mutational changes in cancer cells that arise to develop resistance to a given therapeutic. I'd imagine this to start showing up in earnest given a reliable way to shut down ALT; absent that, there isn't much of a forcing function on the cancer evolution.

Posted by: Reason at June 6th, 2019 7:23 AM
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