Fight Aging!

The next stage in this year's SENS rejuvenation research funding initiatives launches today: the SENS Research Foundation is crowdfunding a search for drug candidates and mechanisms that can attack all ALT cancers, those that abuse the alternative lengthening of telomeres (ALT) processes to grow. This is a part of the OncoSENS program, which seeks to produce the grounding for a universal cancer treatment platform, based on the one commonality known to be shared by all cancers, which is that cancer cells must lengthen their telomeres, one way or another. You may recall coverage of the SENS Research Foundation ALT research in the scientific press last year. Given the ability to turn off telomere lengthening, then that is also the ability to turn off cancer, any cancer. The cost of mitigating the potential side-effects of this approach, such as loss of stem cell activity, is a small line item in comparison to the cost of present cancer research strategies, as they produce treatments that are expensive to develop, but more importantly can usually only be used for one of the hundreds of subtypes of cancerous growth. To make real progress in cancer, the research community must instead attack the shared vulnerabilities in all cancers, so as to greatly reduce the cost of building viable treatments that will work for many patients, not just a few.

Like other SENS initiatives, OncoSENS, and ALT targeting in particular, is focused on funding an area of research important to aging and longevity science that is presently languishing, largely neglected by the mainstream of the scientific community. There are many such dead zones in the sciences, where the potential for great progress is left untended, usually for no good reason, and too few people are willing to step in to do something about it. The SENS Research Foundation and Methuselah Foundation before it have in a number of cases helped to generate active research and development communities from these dead zones through advocacy and targeted philanthropic funding, and seek to do the same here. A robust and cost-effective cure for cancer is a necessary part of the future rejuvenation toolkit, and prevention of telomere lengthening is a good candidate for the job. The ALT cancer research crowdfunding campaign can be found at Lifespan.io, and I encourage you to show your support; this is yet another field that might blossom in the years ahead thanks to exactly this sort of effort.

OncoSENS: Control ALT, Delete Cancer

Of all the risk factors associated with cancer: obesity, smoking, sun exposure etc., there is none more universal than aging. Therefore it is of paramount importance to develop new anti-cancer approaches to meet the humanitarian and economic challenges associated with our aging global population. One such approach is to target cancers that employ a particular mechanism to achieve cellular immortality - Alternative Lengthening of Telomeres, or "ALT".

Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either enters senescence or undergoes apoptosis (programmed cell death). Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Most cancer cells bypass this failsafe by synthesizing new telomeres using the enzyme telomerase. Several therapies targeting this well-described telomerase-based pathway are in the advanced stages of clinical development, but as with any cancer therapy there is the potential for development of resistance against telomerase-based strategies to defeat cancer. Studies using mice and human cancer cell lines have demonstrated that cancer can overcome the loss of telomerase by using a telomerase-independent mechanism called alternative lengthening of telomeres (ALT). Furthermore, existing tumor cells in mice have also been observed to switch over to the ALT pathway as a result of telomerase-inhibiting treatment. It is therefore plausible that telomerase-dependent cancer treatments will introduce selective pressures in human tumors to activate the ALT pathway and/or select for cells already using ALT within the tumor. This makes the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches.

There are currently no ALT-targeted anti-cancer therapeutics, however, largely because this process is much less well understood. 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, by our collaborator, Dr. Jeremy Henson, back in 2009. C-circles are an unusual type of circular DNA sequences 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 OncoSENS research team at the SENS Research Foundation, in collaboration with Dr. Jeremy Henson at the University of New South Wales in Australia, has developed a novel version of the C-circle assay that can be fully automated using robotic liquid handlers, making it now feasible to perform robust high-throughput screenings to search for chemical modulators of the ALT pathway.

The goal of this project is to screen a library of about 115,000 compounds containing structurally diverse, medicinally active, and cell permeable drugs from a variety of fields of medicine (oncology, cardiology, and immunology, etc.), for inhibitors of the ALT pathway. The crucial advantage of making use of such drug libraries, which are richly documented and contain some FDA approved compounds, is that once hits are identified and validated using our ALT-specific assays they can potentially be repurposed for the treatment of patients with ALT cancers through cheaper, faster and safer preclinical and clinical validation protocols. Our initial goal of $60,000 will allow us to test a significant subgroup of this library, and reaching a stretch goal of $200,000 will allow us to test them all.

While a few groups are presently working on inhibition of telomerase-based telomere lengthening in cancer, and the majority of cancers use telomerase rather than ALT when left to their own devices, as noted above it is clearly the case that ALT inhibition is an essential part of this approach to a universal cancer therapy. Unfortunately, the SENS Research Foundation is one of the very few groups funding any significant work in this area of cancer research. Still, there is a real opportunity here, and with the falling cost of early stage research, a great deal of useful work can be accomplished with comparatively little funding. Working through the most promising parts of standard drug libraries should produce leads on drug candidates and mechanisms for interfering with ALT that will attract the interest of other investigators. Taking this step is necessary if the telomere interdiction approach to cancer is to grow, and funding the important work that others do not is exactly how the SENS Research Foundation has produced considerable success in other areas of aging research.

I really can't overstate how important it is to change the nature of cancer research, steering the scientific community away from the approach of one costly research project per subtype of cancer and towards the production of a single technology that can attack all cancers with minimal adjustment. I will be donating to this OncoSENS crowdfunding initiative, and I encourage you to do so as well. It is an rare chance to nudge cancer researchers towards a better, more effective strategic direction, to help start an avalanche that will pay off greatly in the years ahead, with therapies that can target all forms of cancer.