Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

Xiang Chen; Elizabeth Stewart; Anang A. Shelat; Chunxu Qu; Armita Bahrami; Mark Hatley; Gang Wu; Cori Bradley; Justina McEvoy; Alberto Pappo; Sheri Spunt; Marcus B. Valentine; Virginia Valentine; Fred Krafcik; Walter H. Lang; Monika Wierdl; Lyudmila Tsurkan; Viktor Tolleman; Sara M. Federico; Chris Morton; Charles Lu; Li Ding; John Easton; Michael Rusch; Panduka Nagahawatte; Jianmin Wang; Matthew Parker; Lei Wei; Erin Hedlund; David Finkelstein; Michael Edmonson; Sheila Shurtleff; Kristy Boggs; Heather Mulder; Donald Yergeau; Steve Skapek; Douglas S. Hawkins; Nilsa Ramirez; Philip M. Potter; John A. Sandoval; Andrew M. Davidoff; Elaine R. Mardis; Richard K. Wilson; Jinghui Zhang; James R. Downing; Michael A. Dyer

doi:10.1016/j.ccr.2013.11.002

Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

Xiang Chen, Elizabeth Stewart, Anang A. Shelat, Chunxu Qu, Armita Bahrami, Mark Hatley, Gang Wu, Cori Bradley, Justina McEvoy, Alberto Pappo, Sheri Spunt, Marcus B. Valentine, Virginia Valentine, Fred Krafcik, Walter H. Lang, Monika Wierdl, Lyudmila Tsurkan, Viktor Tolleman, Sara M. Federico, Chris MortonCharles Lu, Li Ding, John Easton, Michael Rusch, Panduka Nagahawatte, Jianmin Wang, Matthew Parker, Lei Wei, Erin Hedlund, David Finkelstein, Michael Edmonson, Sheila Shurtleff, Kristy Boggs, Heather Mulder, Donald Yergeau, Steve Skapek, Douglas S. Hawkins, Nilsa Ramirez, Philip M. Potter, John A. Sandoval, Andrew M. Davidoff, Elaine R. Mardis, Richard K. Wilson, Jinghui Zhang, James R. Downing, Michael A. Dyer

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Abstract

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

Original language	English
Pages (from-to)	710-724
Number of pages	15
Journal	Cancer Cell
Volume	24
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2013.11.002
State	Published - Dec 9 2013

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10.1016/j.ccr.2013.11.002

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Chen, X., Stewart, E., Shelat, A. A., Qu, C., Bahrami, A., Hatley, M., Wu, G., Bradley, C., McEvoy, J., Pappo, A., Spunt, S., Valentine, M. B., Valentine, V., Krafcik, F., Lang, W. H., Wierdl, M., Tsurkan, L., Tolleman, V., Federico, S. M., ... Dyer, M. A. (2013). Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma. Cancer Cell, 24(6), 710-724. https://doi.org/10.1016/j.ccr.2013.11.002

@article{952b2e2838094c8fbf2006c5025bc821,

title = "Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma",

abstract = "Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.",

author = "Xiang Chen and Elizabeth Stewart and Shelat, {Anang A.} and Chunxu Qu and Armita Bahrami and Mark Hatley and Gang Wu and Cori Bradley and Justina McEvoy and Alberto Pappo and Sheri Spunt and Valentine, {Marcus B.} and Virginia Valentine and Fred Krafcik and Lang, {Walter H.} and Monika Wierdl and Lyudmila Tsurkan and Viktor Tolleman and Federico, {Sara M.} and Chris Morton and Charles Lu and Li Ding and John Easton and Michael Rusch and Panduka Nagahawatte and Jianmin Wang and Matthew Parker and Lei Wei and Erin Hedlund and David Finkelstein and Michael Edmonson and Sheila Shurtleff and Kristy Boggs and Heather Mulder and Donald Yergeau and Steve Skapek and Hawkins, {Douglas S.} and Nilsa Ramirez and Potter, {Philip M.} and Sandoval, {John A.} and Davidoff, {Andrew M.} and Mardis, {Elaine R.} and Wilson, {Richard K.} and Jinghui Zhang and Downing, {James R.} and Dyer, {Michael A.}",

note = "Funding Information: We thank S. Frase for assistance with electron microscopy, B. Vadodaria for technical assistance, and A. McArthur for editing the manuscript. This work was supported, in part, by a Cancer Center Support grant (CA21765) from the National Cancer Institute, National Institutes of Health grants (EY014867, EY018599, and CA168875) to M.A.D., and the American Lebanese Syrian Associated Charities. M.A.D. is a Howard Hughes Medical Institute Investigator. The WGS was supported as part of the SJCRH–Washington University Pediatric Cancer Genome Project. Finally, we thank John and Andra Tully and the Tully Family Foundation for generous support of Pediatric Solid Tumor Research at SJCRH. ",

year = "2013",

month = dec,

day = "9",

doi = "10.1016/j.ccr.2013.11.002",

language = "English",

volume = "24",

pages = "710--724",

journal = "Cancer Cell",

issn = "1535-6108",

number = "6",

}

Chen, X, Stewart, E, Shelat, AA, Qu, C, Bahrami, A, Hatley, M, Wu, G, Bradley, C, McEvoy, J, Pappo, A, Spunt, S, Valentine, MB, Valentine, V, Krafcik, F, Lang, WH, Wierdl, M, Tsurkan, L, Tolleman, V, Federico, SM, Morton, C, Lu, C, Ding, L, Easton, J, Rusch, M, Nagahawatte, P, Wang, J, Parker, M, Wei, L, Hedlund, E, Finkelstein, D, Edmonson, M, Shurtleff, S, Boggs, K, Mulder, H, Yergeau, D, Skapek, S, Hawkins, DS, Ramirez, N, Potter, PM, Sandoval, JA, Davidoff, AM, Mardis, ER, Wilson, RK, Zhang, J, Downing, JR & Dyer, MA 2013, 'Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma', Cancer Cell, vol. 24, no. 6, pp. 710-724. https://doi.org/10.1016/j.ccr.2013.11.002

TY - JOUR

T1 - Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

AU - Chen, Xiang

AU - Stewart, Elizabeth

AU - Shelat, Anang A.

AU - Qu, Chunxu

AU - Bahrami, Armita

AU - Hatley, Mark

AU - Wu, Gang

AU - Bradley, Cori

AU - McEvoy, Justina

AU - Pappo, Alberto

AU - Spunt, Sheri

AU - Valentine, Marcus B.

AU - Valentine, Virginia

AU - Krafcik, Fred

AU - Lang, Walter H.

AU - Wierdl, Monika

AU - Tsurkan, Lyudmila

AU - Tolleman, Viktor

AU - Federico, Sara M.

AU - Morton, Chris

AU - Lu, Charles

AU - Ding, Li

AU - Easton, John

AU - Rusch, Michael

AU - Nagahawatte, Panduka

AU - Wang, Jianmin

AU - Parker, Matthew

AU - Wei, Lei

AU - Hedlund, Erin

AU - Finkelstein, David

AU - Edmonson, Michael

AU - Shurtleff, Sheila

AU - Boggs, Kristy

AU - Mulder, Heather

AU - Yergeau, Donald

AU - Skapek, Steve

AU - Hawkins, Douglas S.

AU - Ramirez, Nilsa

AU - Potter, Philip M.

AU - Sandoval, John A.

AU - Davidoff, Andrew M.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Zhang, Jinghui

AU - Downing, James R.

AU - Dyer, Michael A.

N1 - Funding Information: We thank S. Frase for assistance with electron microscopy, B. Vadodaria for technical assistance, and A. McArthur for editing the manuscript. This work was supported, in part, by a Cancer Center Support grant (CA21765) from the National Cancer Institute, National Institutes of Health grants (EY014867, EY018599, and CA168875) to M.A.D., and the American Lebanese Syrian Associated Charities. M.A.D. is a Howard Hughes Medical Institute Investigator. The WGS was supported as part of the SJCRH–Washington University Pediatric Cancer Genome Project. Finally, we thank John and Andra Tully and the Tully Family Foundation for generous support of Pediatric Solid Tumor Research at SJCRH.

PY - 2013/12/9

Y1 - 2013/12/9

N2 - Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

AB - Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

UR - http://www.scopus.com/inward/record.url?scp=84891953948&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2013.11.002

DO - 10.1016/j.ccr.2013.11.002

M3 - Article

C2 - 24332040

AN - SCOPUS:84891953948

SN - 1535-6108

VL - 24

SP - 710

EP - 724

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

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