Control ALT, Delete Cancer: Coverage of the SENS Research Foundation OncoSENS Project

It is always pleasant to see scientific media outlets treat the work of the SENS Research Foundation with the respect it deserves. The Foundation staff are engaged in a modest range of research projects, usually in collaboration with major laboratories in the US and Europe, all of which relate to the defeat of degenerative aging. How to achieve that goal? By repairing the cellular and molecular damage that causes aging, and by cutting off major avenues of dysfunction at the simplest possible point of commonality in the underlying biochemistry. In most cases that point of commonality is the damage: for example you might think of the accumulation of metabolic waste products such as amyloid between cells and lipofusin inside cells. Those waste products can in principle be cleared, removing their effects. For cancer, however, there is a different story.

Cancer is the result of nuclear DNA damage. This damage accumulates in a stochastic fashion across a lifetime, and the more of it you have the greater your odds on any given day of a cell running amok and successfully evading the immune system to generate a tumor. Of course it doesn't help that the immune system is itself also increasingly damaged and subject to dysfunction with advancing age, but cancer is fundamentally an age-related condition because of growth in DNA damage over time. Repairing this damage isn't a near term feasible project. Researchers can fairly clearly envisage and model the sort of molecular nanorobotics that would be needed, but their creation is somewhere several cycles ahead in the march of progress.

So what to do in the meanwhile? The challenge of cancer lies in the fact that it is a broad category covering many, many forms of dysfunctional cellular mechanisms. A treatment built using even the best of today's drug discovery approaches may only work on one of the thousands of classified forms of cancer, and an individual tumor of that type may very well rapidly evolve its way out of being vulnerable in any given treated patient. There is, however, one point of commonality shared by all cancerous cells. They must all continually lengthen their telomeres; if deprived of all means to do so, they will cease to replicate in short order upon reaching the Hayflick limit. Each cell division shortens telomeres and cells with very short telomeres will self-destruct or become senescent. All cancers abuse telomerase or the comparatively poorly understood alternative lengthening of telomeres (ALT) mechanisms in order to continue to exist. Here, then, is the root to strike at, the field from which the ultimate cure for cancer may emerge.

While a number of research groups are hard at work on safely disrupting telomerase activity as a cancer treatment, the SENS Research Foundation is largely focused on the building the tools needed to do the same for ALT:

Control ALT, Delete Cancer

Cellular immortality is a hallmark of cancers that distinguishes them from normal tissue. Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called the telomeres, gets shorter. When the telomeres shorten too much, an alarm signal is generated, and the cell permanently stops dividing and enters senescence or undergoes apoptosis. Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Cancer cells, on the other hand, can become immortalized by activating a telomere maintenance mechanism (TMM) that counteracts telomere shortening by synthesizing new telomeric DNA from either an RNA template using the enzyme telomerase or a DNA template using a mechanism called alternative lengthening of telomeres (ALT).

Because the presence of a TMM is an almost universal characteristic of cancer cells, and experimentally repressing these mechanisms results in cancer cell senescence or death, TMMs may be useful targets in treating cancer. Indeed, several therapies targeting the well-described telomerase-based pathway are in the advanced stages of clinical development. There are currently no ALT-targeted therapeutics, however, largely because this process is less well understood.

In contrast to telomerase-driven telomere lengthening, which does occur in the stem cells of healthy tissues and organs, ALT activity is not found in normal human postnatal tissues - a fact that would allow for more-effective dosing with minimal side effects. And based on the conservative estimate that 10 percent of cancers employ an ALT strategy to achieve cellular immortality, there are about 1.4 million new cases and 820,000 deaths globally due to ALT cancers every year. These include some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers. Clearly, targeting ALT is a very attractive strategy in the development of novel cancer therapies.

The development of ALT-targeted therapies is quite challenging, however. Unlike the telomerase pathway, the ALT mechanism has no known specific enzyme activity, and all the enzymes identified to date that play a role in ALT are also essential to normal cellular pathways. The presence of ALT activity has often been inferred from detecting telomere-related phenotypes, such as long and heterogeneous telomere length distributions or ALT-associated promyelocytic leukemia nuclear bodies (APB), which indicate the abnormal presence of telomeres inside a complex formed from otherwise ubiquitous nuclear proteins. These markers are not entirely satisfactory, as they can sometimes yield inaccurate results and are not practical for high-throughput applications or clinical laboratories.

A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle. C-circles are an unusual type of circular DNAs that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The development of the C-circle assay as well as improvements to the APB assay could, in the near future, make it feasible to perform robust high-throughput screenings to search for modulators of the ALT pathway, which will greatly speed the pace of discovery in this field. Further research will no doubt lead to a more complete mechanistic understanding of this phenomenon and to the first ALT-specific therapies against cancer. Controlling ALT could very well help delete the burden of cancer from society.

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