Abstract 4681: Inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) as a strategy for targeted therapy in Ewing's sarcoma

Abstract

Abstract The Ewing's sarcoma family of tumors (ESFTs) are aggressive malignancies which frequently harbor EWS-FLI1 or EWS-ERG genomic fusions. Here, we demonstrate that these fusion products interact with, and depend on, poly (ADP-ribose) polymerase 1 (PARP1), a DNA damage response protein and transcriptional co-regulator. This interaction occurs in a DNA-independent manner. ESFT cell lines and xenografts are preferentially sensitive to PARP1 inhibition, and the addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete response of all treated tumors in an EWS-FLI1 ESFT xenograft model. PARP inhibition blocked Ewing's cell line, but not control osteosarcoma or rhabdomyosarcoma cell line invasion, as well as the formation of lung metastasis in a xenograft model of ESFT. Mechanistically, the EWS-FLI1 and EWS-ERG fusions induce DNA damage, which is potentiated by PARP1 inhibition in ESFT cell lines. In a positive feedback loop, EWS-FLI1 fusions maintain the expression of PARP1 by direct regulation of the PARP1 promoter. This regulation is independently supported by a gene expression array data set of 20 ESFT patient tumors (Spearman r = 0.8165). Finally, because front-line therapy for this disease includes an intense regimen of five cytotoxic chemotherapy agents from which patients can quickly relapse with even more aggressive disease, we studied the effect of PARP inhibition in two Ewing's sarcoma cell line models derived after patient relapse. Importantly, these two cell lines maintained a preferential sensitivity to PARP1 inhibition despite their general chemoresistance. These findings suggest that targeting the EWS-FLI1: PARP1 interaction axis is a promising therapeutic strategy for the Ewing's sarcoma family of tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4681. doi:1538-7445.AM2012-4681