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. Snyder; Suresh Thiagarajan; Abbas Shirinifard; Andras Sablauer; Anang A. Shelat; Michael A. Dyer

doi:10.1016/j.celrep.2014.09.028

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

145 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 (PARP_is). PARP_i-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 PARP_is 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 PARP_is; it was also better tolerated than combinations with temozolomide. Combining PARP_is with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.

Original language	English
Pages (from-to)	829-840
Number of pages	12
Journal	Cell Reports
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.09.028
State	Published - 2014

Bibliographical note

Publisher Copyright:
© 2014 The Authors.

Funding

We thank Jieun Kim for assistance with PET-CT and MRI, Angela McArthur for editing the manuscript, Fred Krafcik for help with cell screening, and David Finkelstein for assistance with bioinformatics analysis. This work was supported, in part, by a grant from Abbvie. It was also supported by a grant from Cancer Center Support (CA21765) from the NCI, grants to M.A.D. from the NIH (EY014867 and EY018599 and CA168875), and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. was also supported by a grant from Alex’s Lemonade Stand Foundation for Childhood Cancer and HHMI. Finally, we thank John and Andra Tully and the Tully Family Foundation for generous support of Pediatric Solid Tumor Research at St. Jude Children’s Research Hospital.

Funders	Funder number
Markey Cancer Center's Cancer Center Support	CA21765
National Institutes of Health (NIH)	CA168875, EY014867
Howard Hughes Medical Institute
National Eye Institute (NEI)	R01EY018599
National Childhood Cancer Registry – National Cancer Institute
Alex's Lemonade Stand Foundation for Childhood Cancer
AbbVie
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2014.09.028

Cite this

Stewart, E., Goshorn, R., Bradley, C., Griffiths, L. M., Benavente, C., Twarog, N. R., Miller, G. M., Caufield, W., Freeman, B. B., Bahrami, A., Pappo, A., Wu, J., Loh, A., Karlström, Å., Calabrese, C., Gordon, B., Tsurkan, L., Hatfield, M. J., Potter, P. M., ... Dyer, M. A. (2014). Targeting the DNA repair pathway in Ewing sarcoma. Cell Reports, 9(3), 829-840. https://doi.org/10.1016/j.celrep.2014.09.028

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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.",

author = "Elizabeth Stewart and Ross Goshorn and Cori Bradley and Griffiths, \{Lyra M.\} and Claudia Benavente and Twarog, \{Nathaniel R.\} and Miller, \{Gregory M.\} and William Caufield and Freeman, \{Burgess B.\} and Armita Bahrami and Alberto Pappo and Jianrong Wu and Amos Loh and {\AA}sa Karlstr{\"o}m and Chris Calabrese and Brittney Gordon and Lyudmila Tsurkan and Hatfield, \{M. Jason\} and Potter, \{Philip M.\} and Snyder, \{Scott E.\} and Suresh Thiagarajan and Abbas Shirinifard and Andras Sablauer and Shelat, \{Anang A.\} and Dyer, \{Michael A.\}",

note = "Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

doi = "10.1016/j.celrep.2014.09.028",

language = "English",

volume = "9",

pages = "829--840",

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Stewart, E, Goshorn, R, Bradley, C, Griffiths, LM, Benavente, C, Twarog, NR, Miller, GM, Caufield, W, Freeman, BB, Bahrami, A, Pappo, A, Wu, J, Loh, A, Karlström, Å, Calabrese, C, Gordon, B, Tsurkan, L, Hatfield, MJ, Potter, PM, Snyder, SE, Thiagarajan, S, Shirinifard, A, Sablauer, A, Shelat, AA & Dyer, MA 2014, 'Targeting the DNA repair pathway in Ewing sarcoma', Cell Reports, vol. 9, no. 3, pp. 829-840. https://doi.org/10.1016/j.celrep.2014.09.028

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AU - Stewart, Elizabeth

AU - Goshorn, Ross

AU - Bradley, Cori

AU - Griffiths, Lyra M.

AU - Benavente, Claudia

AU - Twarog, Nathaniel R.

AU - Miller, Gregory M.

AU - Caufield, William

AU - Freeman, Burgess B.

AU - Bahrami, Armita

AU - Pappo, Alberto

AU - Wu, Jianrong

AU - Loh, Amos

AU - Karlström, Åsa

AU - Calabrese, Chris

AU - Gordon, Brittney

AU - Tsurkan, Lyudmila

AU - Hatfield, M. Jason

AU - Potter, Philip M.

AU - Snyder, Scott E.

AU - Thiagarajan, Suresh

AU - Shirinifard, Abbas

AU - Sablauer, Andras

AU - Shelat, Anang A.

AU - Dyer, Michael A.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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AN - SCOPUS:84919705139

SN - 2211-1247

VL - 9

SP - 829

EP - 840

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

Targeting the DNA repair pathway in Ewing sarcoma

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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