Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma

Abstract

Purpose of review: In 2012, two publications revealed a particular sensitivity of Ewing sarcoma cells to the inhibition of poly(ADP-ribose) polymerase (PARP). This review updates the reader on PARP function, the development of PARP inhibitors (PARPi) and the evidence for targeting PARP in Ewing sarcoma. It concludes with a description of ongoing/emerging PARPi clinical trials in patients with Ewing sarcoma.

Recent findings: PARP has a major role in DNA repair, and is a transcription regulator. The oncoprotein in Ewing sarcoma, EWS-FLI1, is proposed to interact with PARP-1, driving PARP-1 expression, which further promotes transcriptional activation by EWS-FLI1. Thus, there are two rationales for PARPi in the treatment of Ewing sarcoma: to disrupt the interaction between EWS-FLI1 and PARP, and for chemo-potentiation or radio-potentiation. The first clinical trial with a single agent PARPi failed to show significant responses, but preclinical evidence for combinations of PARPi with chemotherapy or radiotherapy is very promising.

Summary: Despite initial excitement for the potential of PARPi as single agent therapy in Ewing sarcoma, the emerging preclinical data now strongly support testing PARPi in combination with chemo/radiotherapy clinically.

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FIGURE 1

Proposed model for interaction of PARP-1 and EWS fusion genes and the potential role for PARPi. EWS fusion gene (exemplified by EWS FLI1) promotes PARP-1 expression, which in turn promotes EWS FLI1 transcriptional activation, creating a positive feedback loop that promotes EWS FLI1-driven malignancy. EWS FLI1 expression results in higher levels of DNA damage that requires PARP-1 for repair. Temozolomide, irinotecan/topotecan and ionizing radiation all cause DNA damage that is repaired in a PARP-dependent manner. PARPi may have single-agent activity in Ewing sarcoma by blocking the positive feedback loop thereby removing the oncogenic driving force, and inhibiting the repair of EWS FLI1-generated DNA damage. PARPi increase the efficacy of temozolomide, irinotecan/topotecan and ionizing radiation by inhibiting repair of the DNA damage they cause. PARP, poly(ADP-ribose) polymerase; PARPi, poly(ADP-ribose) polymerase inhibitor.