Cell Reports (Nov 2014)
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 III,
- Armita Bahrami,
- Alberto Pappo,
- Jianrong Wu,
- Amos Loh,
- Åsa Karlström,
- Chris Calabrese,
- Brittney Gordon,
- Lyudmila Tsurkan,
- M. Jason Hatfield,
- Philip M. Potter,
- Scott E. Snyder,
- Suresh Thiagarajan,
- Abbas Shirinifard,
- Andras Sablauer,
- Anang A. Shelat,
- Michael A. Dyer
Affiliations
- Elizabeth Stewart
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Ross Goshorn
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Cori Bradley
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Lyra M. Griffiths
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Claudia Benavente
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Nathaniel R. Twarog
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Gregory M. Miller
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- William Caufield
- Preclinical Pharmacokinetics Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Burgess B. Freeman III
- Preclinical Pharmacokinetics Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Armita Bahrami
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Alberto Pappo
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Jianrong Wu
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Amos Loh
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Åsa Karlström
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Chris Calabrese
- Animal Imaging Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Brittney Gordon
- Animal Imaging Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Lyudmila Tsurkan
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- M. Jason Hatfield
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Philip M. Potter
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Scott E. Snyder
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Suresh Thiagarajan
- Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Abbas Shirinifard
- Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Andras Sablauer
- Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Anang A. Shelat
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Michael A. Dyer
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- DOI
- https://doi.org/10.1016/j.celrep.2014.09.028
- Journal volume & issue
-
Vol. 9,
no. 3
pp. 829 – 840
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 DNA-damaging 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.
