When Ewing sarcoma, a tumour of the bone, spreads to other parts of the body, it is difficult to treat and usually fatal. This project builds on previous work that has identified a promising new approach to treatment, combining two different types of drugs.
If successful, the team will take the new therapy forward to clinical trial.
The genetics of familial leukaemia
Dr Ariadna Mendoza
UCL Cancer Institute
London, WC1E 6DD
29 March 2013
Ewing sarcoma (ES) is the second most common bone tumour in children and adolescents. One third of patients do not survive five years from diagnosis. Most of the deaths are due to metastatic disease – i.e. disease that has spread to other parts of the body.
There is an urgent need to identify the ‘drivers’ of metastasis in ES and new therapies that will specifically target metastases in these patients.
In previous work, also funded by Children with Cancer UK, Dr Mendoza and colleagues have shown that high expression of a gene known as ERBB4 is directly linked to metastasis and reduced survival of ES patients. They have shown that inhibition of ERBB4 reduces metastasis and makes metastatic/chemoresistant ES cells more responsive to chemotherapy.
PARP is a family of proteins involved in a number of critical cellular processes including DNA damage repair. It has also recently emerged as a prospective therapeutic target in ES as inhibition of PARP intensifies DNA damage in ES cells.
Dr Mendoza and colleagues have demonstrated that combined inhibition of ERBB4 and PARP has a greater effect and is more effective at eliminating ES cells than inhibition of either target alone. They have selected drugs that are currently undergoing or have already undergone phase 2 clinical trial in adult patients with advanced solid tumours and will undertake a programme of pre-clinical experiments to build the evidence necessary to take this approach forward to phase 1 clinical trial in ES patients.
If this combination therapy proves effective in reducing the extent of disease, it will improve the quality of life and the life expectancy of children with metastatic ES who currently have a very poor prognosis. In addition, anti-ERBB4 inhibitors may be less toxic than chemotherapy and if used in combination with PARP inhibitors, this may reduce tumour resistance and allow for lower doses of drugs, further reducing risk of toxicity.
The team at UCL is internationally known for their work on sarcoma. Members of the team have worked on the ERBB4/ Ewing sarcoma project for a number of years and are in a good position to take it to the next level. They have good links with the team at Great Ormond Street Hospital responsible for development of Phase 1 and 2 clinical trials and are therefore well-placed to develop the potential clinical protocols.