Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors

Abstract

Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models. The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (RD-ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates. Olaparib induced growth inhibition, median (range) IC50 = 3.6 (1-33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In RD-ES and NGP xenografts, olaparib inhibited PAR activity by 88-100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated. In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.