Entry for:Inspire Australia Research Competition
Some of the hardest to treat cancers use the ALT cancer mechanism, which is not found in normal cells, providing a specific target for the development of new treatments. We will use our patented technology for measuring ALT activity to generate the first ALT-targeted cancer cures.
For this project we will automate our technique for measuring ALT activty, the C-Circle Assay, and use this to screen a library of 115,000 compounds. Compounds that decrease ALT activity could potentially lead to cures that selectively kill ALT+ cancer cells with negligible side-effects. Any chemicals discovered by this project to be potential ALT-targeted cancer cures will be optimized and tested in pre-clinical models, in a subsequent project.
Automated screening of compound libraries that represent the potential cure universe is generally the most successful strategy for novel drug discovery, with success rates reported above 95%. This mass screening approach has been used successfully for ALT’s sister immortality mechanism, and our C-Circle Assay now makes this approach possible for ALT. We have proven the C-Circle Assay’s capability to identify drugs that inhibit ALT cancer activity in a small manual screen, which successfully identified a compound that inhibits ALT and kills ALT+ cancer cells.
This project is expected to take 12 months. The first nine months will involve using the ALT-targeted anti-cancer drugs that we have identified in the manual screen for the optimization of the automated version of the C-Circle Assay. The last three months will involve setting up the automated C-Circle Assay and carrying out the screen on the robotic system at the Drug Discovery Unit, Children’s Cancer Institute, Lowy Cancer Research Centre, University of NSW. Any compounds identified as inhibiting ALT will be further evaluated on a panel of ALT positive (ALT+) cancer cells, ALT negative cancer cells and normal cells. We will confirm inhibition of ALT activity and their ability to kill the ALT+ cancer cells without harming normal cells.
3. Additional Details
New Cancer Cures
Targeted cancer therapeutics is the fastest growing area in cancer pharmacology. Conventional therapies do not have satisfactory selectivity for cancer cells and harm normal cells as well, which can limit their ability to achieve a cure and causes serious adverse health effects in survivors, such as sterility, organ failure, secondary cancer and (in children) growth and neurocognitive deficits.
Targeted cancer therapies attack cancer-specific targets and therefore have minimal side-effects and can be used at more effective doses. The most ubiquitous cancer-specific target is cancer cell immortality.
Cancer immortality mechanism targeted therapeutics target one of the two cancer immortality mechanisms, ALT (Alternative Lengthening of Telomeres) or telomerase. Telomerase-targeted cancer therapeutics are in advanced stage clinical trials and are proving to have minimal side-effects2, due to the high cancer selectivity of cancer immortality mechanisms. The telomerase mechanism was made accessible for the development of therapeutics and diagnostics by the discovery of the telomerase enzyme in 1984, which received the 2009 Nobel Prize for Medicine.
ALT-targeted therapeutics is an undeveloped and, until recently, an inaccessible resource.
Over one million of all the cancers diagnosed each year (worldwide) rely on the ALT mechanism and not the telomerase mechanism3, and therefore will not be treated by telomerase-targeted therapies. These include half of all pediatric brain cancers, one quarter of all adult brain cancers, half of some sarcomas (such as bone cancer) and 5-10% of breast and lung cancers3.
The ALT mechanism has been inaccessible to therapeutic development due to the lack of a measure the amount of ALT activity. We have now achieved this.
We identified that the lack of an ALT specific molecule was the critical problem, proposed the existence of a novel biomarker in cells with ALT activity and proved its existence.
Subsequently, we identified the most useful subset of this biomarker, which we named C-Circles. These unusual molecules consist of partially double-stranded circles of DNA that are derived from the ends of our chromosomes (telomeres). We invented the C-Circle Assay (Fig. 1) that distinguishes ALT[+] and [-] tumours using only nanogram quantities of genomic DNA, is rapidly responsive to changes in ALT activity, and showed that it can detect C-Circles in the blood of patients with ALT[+] bone cancer (Fig. 1)1. We have thus succeeded in inventing technology that is opening up the ALT mechanism to development of therapeutics and diagnostics, and is a crucial tool for all research labs investigating the ALT mechanism.