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Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma

Lookup NU author(s): Dr Britta Vormoor, Professor Nicola Curtin

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Purpose of reviewIn 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 findingsPARP 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.SummaryDespite 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.


Publication metadata

Author(s): Vormoor B, Curtin NJ

Publication type: Review

Publication status: Published

Journal: Current Opinion in Oncology

Year: 2014

Volume: 26

Issue: 4

Pages: 428-433

Print publication date: 01/07/2014

ISSN (print): 1040-8746

ISSN (electronic): 1531-703X

Publisher: LIPPINCOTT WILLIAMS & WILKINS

URL: http://dx.doi.org/10.1097/CCO.0000000000000091

DOI: 10.1097/CCO.0000000000000091


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