Ewing’s sarcoma is the second most commonly diagnosed primary bone cancer, it mostly affects young people under 20 years. Despite recent developments in treatment half of patients die within 5 years. Ewing’s sarcomas are commonly treated with radiotherapy and two new drugs that are being used are temozolomide and the Topo I poisons.

Standard radiotherapy and chemotherapies are used in the treatment of cancers because they cause damage to a cell’s DNA. At sufficiently high doses, damage can be fatal, causing the destruction of the cell, a reduction in the number of cancerous cells and hopefully patient remission. However because some DNA damage is caused by everyday life we have evolved lots of ways to repair DNA. Some of these repair pathways are increased in tumour cells, which can make them resistant to treatment. The enzyme, PARP, plays an important part in the repair of some types of damage by a process called base excision repair, or BER. PARP activity is reported to be increased in Ewing’s sarcoma. We have developed drugs that inhibit PARP and increases the anti-cancer activity of radiotherapy, temozolomide and topo I poisons in laboratory studies. Through a collaboration with CR UK and Pfizer we have taken one very active PRAP inhibitor (AG014699) into early clinical trials in combination with temozolomide. AG014699 caused a remarkable reduction in patients PARP activity, was not toxic and appeared to increase the effectiveness of temozolomide. We wish to show that we can also increase the anti-cancer activity of radiotherapy, temozolomide and topo I poisons in Ewing’s sarcoma.

We also wish to investigate the possibility that our PARP inhibitor will selectively target Ewing’s sarcoma cells over normal cell tissue. We believe that the mutation that causes Ewing’s sarcoma may reduce its ability to repair DNA by a different pathway called homologous recombination, or HR. The BER and HR pathways appear to be complimentary and cells can live without one or the other, but die if both pathways are lost. We have discovered that cells lacking HR can be killed by PRAP inhibitors alone, without the need for highly toxic chemotherapy drugs or radiotherapy. This is exciting because a PARP inhibitor will only kill the tumour cells that have the defect in HR and should not cause side-effects. PARP inhibitors are now showing promising activity in clinical trial in breast and ovarian cancer patients with mutations in the HR genes, BRCA1 and BRCA2. If we can prove that Ewing’s cells also have HR defects, and hence are killed by PARP inhibitors alone, it may mean that these patients can be treated with a side-effect-free drug.

Professor Nicola Curtin and Dr Evan Mulligan, University of Newcastle