Professor Nicola Curtin and Dr Evan Mulligan, University of Newcastle (£29,595)
Assessment of the PARP inhibitor AG-014699 as a chemo-potentiating agent and novel therapy in Ewing's sarcoma.
Ewing's sarcoma is the second most commonly diagnosed bone cancer. Radiotherapy(IR) is commonly used and temozolomide(TMZ) and the topoisomerase I (topo I) poisons (topotecan, irinotecan) show encouraging activity. However, despite these recent therapeutic advances five year survival rates remain at 50% highlighting the need for improvement.
PARP inhibitors increase the antitumour activity of IR, TMZ and topo I poisons in a variety of human adult and paediatric cancer models. PARP inhibition prevents the repair of DNA breaks caused by these agents thereby increasing their cytotoxicity. We co-developed AG014699, the first PARP inhibitor to enter clinical trial for cancer therapy. AG014699 inhibited PARP in patients and doubled the reported response rate to TMZ. Our pre-clinical neuroblastoma and medulloblastoma studies supported a successful CR UK NAC application for the first paediatric trial of AG014699. We now wish to determine if AG014699 sensitises Ewing's sarcoma cells to IR, TMZ and topo I poisons. Ewing's sarcoma may also be hyper-sensitive to PARP inhibitors because their characteristic chromosomal translocation may interfere with homologous recombination(HR). Cells with other HR defects (eg BRCA1 and 2) are exquisitely sensitive to PARP inhibitors alone due to synthetic lethality. We now wish to determine HR function and AG014699 cytotoxicity in Ewing's sarcoma cells.
In this pilot study we will focus on Ewing's cell lines known to grow as sub-cutaneous xenografts, so a successful in vitro investigation may be easily translated into pre-clinical studies with the aim of justifying clinical trials of PARP inhibitors in Ewing's patients.
