Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jul;26(4):428-33.
doi: 10.1097/CCO.0000000000000091.

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma

Britta Vormoor  1 , Nicola J Curtin
Affiliations
Free PMC article
Review

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma

Britta Vormoor et al. Curr Opin Oncol. 2014 Jul.
Free PMC article

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.

PubMed Disclaimer

Figures

Box 1
Box 1
no caption available
FIGURE 1
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.
See this image and copyright information in PMC

References

    1. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. Ann Oncol 1998; 9:275–281 - PubMed
    1. Cotteril SJ, Ahrens S, Paulussen M, et al. Prognostic Factors in Ewing's Tumour of Bone: Analysis of 975 Patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. JCO 2000; 18:3108–3114 - PubMed
    1. Stahl M, Ranft A, Paulussen M, et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr Blood Cancer 2011; 57:549–553 - PubMed
    1. Potratz J, Dirksen U, Jürgens H, Craft A. Ewing sarcoma: clinical state of the art. Pediatr Hematol Oncol 2012; 29:1–11 - PubMed
    1. Brenner JC, Feng FY, Han S, et al. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res 2012; 72:1608–1613 - PMC - PubMed

    2. This article first described the interaction of EWS-FLI1 protein with PARP and PARPi as a new treatment strategy for Ewing sarcoma.

Publication types

MeSH terms

Substances