We are testing a diverse drug library to find treatments for ‘ALT’ cancers, those which rely on the Alternative Lengthening of Telomeres, as one important piece of a comprehensive anti-aging strategy is “Let’s Control ALT, Delete Cancer!“
Of all the risk factors associated with cancer, such as obesity, smoking, and sun exposure, 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 lifespan. 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 unusual 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 that are 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, such as oncology, cardiology, and immunology, 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.