Dr Scott Cohen
Children’s Medical Research Institute
$440,047
2025 - 2028
The Research
Standard-of-care chemotherapeutic agents work by causing DNA damage; for a cancer cell to survive treatment with such agents requires DNA repair mechanisms to correct the damage. A region that is particularly sensitive to DNA damage is the ends of chromosomes, called telomeres. Telomeres are the protective caps at the ends of chromosomes and are essential for genomic stability. Telomeres shorten through each cell division, a natural process of healthy ageing, limiting the number of times a cell can divide. However, ~90% of all human cancers, representing virtually every tissue and cancer type, have activated the enzyme telomerase to counteract telomere shortening, allowing cancer cells to divide without limit. Small-molecule telomerase inhibitors have been a promising molecular approach to cancer therapy for three decades, yet no such compounds have entered the clinic.
Research from CMRI has revealed an interdependence between DNA repair mechanisms that are activated in response to DNA damage, and telomerase action at the telomere. These observations provide a mechanistic link between chemotherapeutic agents and telomerase action at the telomere that promotes cancer cell survival, and lead to the testable hypothesis that applying a small-molecule telomerase inhibitor in conjunction with DNA-damaging chemotherapeutic agents will sensitise cancer cells to chemotherapeutics, allowing lower – and hence safer – doses to be applied.
Dr Cohen and Team have identified a small-molecule telomerase inhibitor which will be used to test the hypothesis. A panel of clinical chemotherapeutic agents (for example, cisplatin, adriamycin, 5-fluorouridine, temozolomide) will be applied against cancer-derived cell lines from a wide range of tissues; cell viability will be assessed in the absence and presence of the telomerase inhibitor. The hypothesis predicts that, in the presence of telomerase inhibition, lower doses of chemotherapeutics will be required to induce cancer cell death. These studies in cultured cell lines will then be translated to pre-clinical mouse tumour models.
There is significant potential for this research to have a transformative and far-reaching impact on the treatment of cancer. Telomerase is present in ~90% of cancers, representing cancers of virtually every organ and tissue, making telomerase-based therapies broadly applicable. Because telomerase is undetectable in most normal human cells, telomerase inhibitors are expected to have fewer side effects than current therapies. The mechanistic data linking telomerase with DNA repair at telomeres leads to the hypothesis that telomerase inhibitors will augment existing chemotherapies for increased efficacy through sensitisation, allowing chemotherapies to be applied at lower – and hence safer – doses.
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