There is an urgent need for new treatments to improve outcome for children and young adults with tumours that belong to the Ewing’s sarcoma family of tumour (ESFT). The primary aim of the Candlelighter’s Children’s Cancer Research Group is to understand how these tumours develop and progress, and why current treatments do not produce cures so that we can identify new targets and strategies for more effective treatment of this aggressive disease. Our goal is to increase the number of children that survive this disease and their quality of life. We evaluate whether targets might be potentially useful for the design of new agents to kill ESFT cells using model systems we have established in the laboratory. The effect of any new agent is evaluated alone and in combination with conventional chemotherapeutic strategies, to establish that a new agent will not reduce any benefit from current therapies. What we want to identify are novel agents that have no toxic side-effects, but that in combination with current treatments kill more ESFT cells to increase cure rates. This can best be achieved by focusing on agents that induce cell death through different mechanisms to those used by conventional therapies.

The models we use in the laboratory are excellent tools to test our ideas. However once we have identified a strategy that might be useful to improve the effectiveness of therapy, it is essential we test if this is likely to work in the patient. This is important to ensure that our observations, hypotheses and future areas of work are clinically relevant. Unfortunately analysis of clinical samples is more difficult than work with the models. In part this is because tumours are more heterogenous, containing different cell types including normal cells and tumour cells. This is made more challenging because tumour cells within a tumour can behave differently, reflecting their inherent characteristics but also the tumour microenvironment. For example, in areas where tumour cells are starved of oxygen, cells can adapt and sometimes become resistant to treatment. Ths adaptation may be a factor in the development of drug resistance, contributing to disease progression and relapse.

Telomerase activity is one of the most important biological factors in the development of many cancers, including ESFT where its is overexpressed compared to expression in normal cells. Telomerase stabilises the cancer cell genome and allows the tumour to grow and may be spread to secondary sites within the body. Furthermore our recent studies using model systems have shown that in hypoxia telomerase activity is increased and might contribute to the development of drug resistance. Dissemination of disease and drug resistance are two of the most difficult challenges for successful treatment of ESFT. We have therefore hypothesised that decreasing telomerase activity in ESFT, we may reduce the development of drug resistance and increase the effectiveness of current therapy. Therapies designed to kill cancer cells by exploiting characteristics that are different in the cancer cell compared to the normal cell are likely to have fewer side-effects than most chemotherapies that simply target all highly proliferative cells; this strategy killing highly proliferative normal cells frequently reducing the immune response making children more susceptible to infection and additional diseases. Biological targets might also be informative indicators of how aggressive a tumour is, and so be useful aids for the pathologist and clinician to determine what kind of treatment is likely to be most effective. In the future this approach will allow clinicians to offer treatments that are specific for an individual cancer, which will mean more effective specific treatment, improved survival rates and increased numbers of cures. Funding from the BCRT will allow us to establish robust assays that can be used in tumours to examine the potential role of telomerase activity, hTR and hTERT isoforms in this clinical material. These studies will inform future strategies for the development of novel therapeutics and prognostication.

Professor Susan Burchill, St James’s University Hospital