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Cell Rep. 2014 Nov 6;9(3):829-41. doi: 10.1016/j.celrep.2014.09.028. Epub 2014 Oct 23.

Targeting the DNA repair pathway in Ewing sarcoma.

Author information

1
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Animal Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
9
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: anang.shelat@stjude.org.
10
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: michael.dyer@stjude.org.

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.

PMID:
25437539
PMCID:
PMC4386669
DOI:
10.1016/j.celrep.2014.09.028
[Indexed for MEDLINE]
Free PMC Article

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