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.
This Project will be based in Dr Henson’s Cancer Cell Immortality Laboratory, Level 2 Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of NSW.
For this project we will automate the C-Circle Assay and use this to screen a library of 100,000 molecules. Molecules that decrease C-Circle levels could potentially lead to cures that selectively kill ALT+ cancer cells with negligible side effects. High-throughput screening of molecular libraries is generally the most successful strategy for novel drug discovery, with success rates often reported above 95%. High-throughput screening has been used successfully for ALT’s sister immortality mechanism, and we already have proof of principle results for finding ALT-targeted anticancer drugs with the C-Circle Assay. 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.
- Henson,J.D., Cao,Y.; Huschtscha,L.I.; Chang,A.C.; Au,A.Y.; Pickett,H.A.; Reddel,R.R. (2009). DNA C-Circles are specific and quantifable markers of alternative-lengthening-of-telomeres activity. Nat. Biotechnol. 27, 1181-1185.
- Marian C.O. & Shay J.W. (2009). Prostate tumor-initiating cells: a new target for telomerase inhibition therapy? Biochim Biophys Acta. 1792, 289-96.
- Henson,J.D. and Reddel,R.R. (2010). Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Letters 584, 3800–3811.