Two research grants awarded to Prof Nicola Curtin from the Northern Institute for Cancer Research at Newcastle University investigated the combination of agents that prevent DNA repair with radiotherapy and chemotherapy.
The findings of these 2 projects provided preliminary evidence that a treatment currently used in other cancers such as breast may be beneficial to Ewing sarcoma patients. These drugs, known as PARP inhibitors are now in early phase clinical trials for Ewing sarcoma.
Radiotherapy and chemotherapy drugs kill cancer cells by producing breaks in their DNA. However, cancer cells contain proteins (named DNA-PK and PARP1) that repair the DNA, therefore “undoing” the damage caused by chemotherapy and or radiotherapy.
The premise of this research was to investigate if by combining agents with chemotherapy and radiotherapy, we could increase their effectiveness in killing Ewing sarcoma cells.
Rucaparib is an inhibitor of PARP1 repair protein which is already used in the clinic to treat other cancers. When Rucaparib was used in combination with temozolomide, camptothecin and radiation, the growth of Ewing Sarcoma cells was reduced, compared with using each drug alone. This effect was most profound for temozolomide which had a 29-fold increase in effectiveness.
An inhibitor of DNA-PK repair protein, NU7441, also increased the cytotoxicity of the chemotherapy treatment.
Why is this research important?
These exciting findings indicate that increasing the effectiveness of DNA-damaging agents (chemotherapy and radiotherapy) by stopping DNA-repair, is a promising approach for improving the treatment of Ewing sarcoma.