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Curr Opin Oncol. 2014 Jul;26(4):428-33. doi: 10.1097/CCO.0000000000000091.

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma.

Author information

1
aNewcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University bGreat North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

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.

PMID:
24840521
PMCID:
PMC4059819
DOI:
10.1097/CCO.0000000000000091
[Indexed for MEDLINE]
Free PMC Article

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