Targeting the DNA repair pathway in Ewing sarcoma

Elizabeth Stewart, Ross Goshorn, Cori Bradley, Lyra M. Griffiths, Claudia Benavente, Nathaniel R. Twarog, Gregory M. Miller, William Caufield, Burgess B. Freeman, Armita Bahrami, Alberto Pappo, Jianrong Wu, Amos Loh, Åsa Karlström, Chris Calabrese, Brittney Gordon, Lyudmila Tsurkan, M. Jason Hatfield, Philip M. Potter, Scott E. SnyderSuresh Thiagarajan, Abbas Shirinifard, Andras Sablauer, Anang A. Shelat, Michael A. Dyer

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNAdamaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.

Original languageEnglish
Pages (from-to)829-840
Number of pages12
JournalCell Reports
Volume9
Issue number3
DOIs
StatePublished - 2014

Bibliographical note

Publisher Copyright:
© 2014 The Authors.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Targeting the DNA repair pathway in Ewing sarcoma'. Together they form a unique fingerprint.

Cite this