There is an urgent need for new therapeutic strategies to improve the outcome for children and young adults with tumours that belong to the Ewing’s sarcoma family of tumour (ESFT), this family of tumours includes Ewing’s sarcoma, peripheral primitive neuroectodermal tumour and Askin tumour. The aim of the Candlelighter’s Children’s Cancer Research Group is to identify novel targets and strategies that can be exploited for the development of new more effective treatments, to improve the number of children that survive this disease and their quality of life. Whether potential targets are good strategies to kill cancer cells and if they will increase the effectiveness of current treatments to improve outcome is evaluated in the model systems that we use in the laboratory in the course of our research. By collaborating with clinical colleagues it is possible to take those agents, and agent combinations, that are most effective at killing the cancer cells in our models to be evaluated in clinical trials for improved patient benefit.

Increasingly new therapies are being developed that target specific features of individual cancers, so-called targeted therapy. Through studies of ESFT biology we can identify novel targets that can be exploited in the design of new therapies, and also markers that can be used by the pathologist and clinician to determine how aggressive and extensive the disease in an individual child and what kind of treatment is likely to be most effective. In the future this approach will mean that clinicians will be able to offer treatments that are specific for an individual cancer, which will be more effective treatment, improved survival rates and increased numbers of cures. Improved outcome is likely to be achieved by combination therapies that include conventional chemotherapy or radiotherapy plus novel agents. So that we can kill all cancer cells we aim to design novel therapies that destroy cancer cells by different methods to those used by conventional chemotherapeutic agents. The ideal treatment is one that rapidly kills all cancer cells and has no effect on normal cells so there is no toxicity.

Our recent studies have shown that a compound called fenretinide kills ESFT cells. As a result of this work in the laboratory and since fenretinide has no toxicity in children or adults it is to be used in a clinical study in the UK this year. This study will test the feasibility and compliance when treating children and adolescents with this compound; the principal clinical investigator is Professor Ian Lewis (Paediatric Oncologist, Leeds). It is anticipated that this agent will subsequently be evaluated in a large phase 3 European prospective randomised trial, and improve outcome for patients with ESFT. This has been very exciting however we predict that even more effective treatment strategies with no or minimal toxicity can be achieved if we can understand more about how fenretinide stops tumour growth; this will allow us to design better agents and agent combinations to induce cell death.

The proposed application will investigate the combination of fenretinide plus TRAIL receptor agonist on ESFT growth in mice, a particularly attractive combination as both agents preferentially induce cell kill in tumour cells with little or no effect on normal cells. Furthermore these agents activate cell death in cancer cells by independent pathways, so we anticipate that the combination of these agents will provide a greater cell kill than either agent alone. Since fenretinide increases TRAIL receptor expression, we will also examine the hypothesis that fenretinide enhances the immune response and investigate its effect on natural killer (NK)-cells and NK-cell cytotoxicity. These studies might identify novel combinations and strategies to enhance the death response. Funding from the BCRT will enable a timely evaluation of these hypotheses, and if successful may facilitate rapid progression of novel treatment combinations into clinical trials for ESFT.

Professor Susan Burchill