Abstract 5357: Pediatric preclinical evaluation of the PARP inhibitor olaparib

Abstract

Abstract Purpose: Olaparib (AZD2281) is an oral poly(ADP)-ribose polymerase (PARP) inhibitor in clinical development as a single agent and in combination with cytotoxic therapy in adults with solid malignancies. In BRCA-1 deficient tumors, olaparib concentrations of 30 nM result in significant PARP inhibition (Rottenberg, PNAS, 2008). Adult patients appear to tolerate olaparib doses associated with a Cmax of 10 µM (Fong, NEJM, 2009). We evaluated the interaction of olaparib with commonly used cytotoxic drugs in a panel of pediatric solid tumor cell lines. Methods: In vitro growth inhibition was assessed using the sulforhodamine B assay in pediatric solid tumor cell lines including: osteosarcoma (MG-63), neuroblastoma (NGP), Ewings sarcoma (RD-ES), medulloblastoma (Daoy), and rhabdomyosarcoma (RD). IC50's were determined following a 120 h exposure to vehicle, olaparib, cytotoxic agent (carboplatin, melphalan, irinotecan, doxorubicin, vincristine) or olaparib in combination with each cytotoxic agent. The combination index (CI) of Chou-Talalay was used to test for synergy of combinations. Results: As a single agent, olaparib was cytotoxic in all cell lines studied, with a median (range) IC50 of 1.7 (0.3-5.3) μM. The Ewings sarcoma cell line was the most sensitive line with a mean (SD) IC50 of 0.7 (0.3) μM. The combination of olaparib with melphalan or irinotecan was synergistic (CI < 1), while the addition of olaparib to doxorubicin or carboplatin appeared additive to synergistic (CI < 1). The combination of olaparib and vincristine trended toward antagonism (CI > 1). Conclusions: The addition of olaparib to DNA damaging agents resulted in additive or synergistic growth inhibition in a panel of pediatric solid tumor cell lines. Further preclinical and clinical evaluation to determine if olaparib can enhance the efficacy of current pediatric chemotherapy regimens is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5357. doi:10.1158/1538-7445.AM2011-5357