@article{b21772aa87204fee93adeb155d4ebe3f,
title = "Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses",
abstract = "Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS). We discovered that alveolar RMS occurs further along the developmental program than embryonal RMS. We also identified deregulation of the RAS/MEK/ERK/CDK4/6, G2/M, and unfolded protein response pathways through our integrated analysis. Comprehensive preclinical testing revealed that targeting the WEE1 kinase in the G2/M pathway is the most effective approach in vivo for high-risk RMS. Using integrated analyses, Stewart et al. reveal the developmental origin of rhabdomyosarcoma (RMS) and identify commonly deregulated pathways. Comprehensive preclinical testing helps prioritize agents for future clinical trials and shows WEE1 as a highly effective therapeutic target for high-risk RMS in vivo.",
keywords = "epigenetics, molecular targeted therapy, pediatric cancer, preclinical testing, proteomics, rhabdomyosarcoma",
author = "{St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project} and Elizabeth Stewart and Justina McEvoy and Hong Wang and Xiang Chen and Victoria Honnell and Monica Ocarz and Brittney Gordon and Jason Dapper and Kaley Blankenship and Yanling Yang and Yuxin Li and Shaw, {Timothy I.} and Cho, {Ji Hoon} and Xusheng Wang and Beisi Xu and Pankaj Gupta and Yiping Fan and Yu Liu and Michael Rusch and Lyra Griffiths and Jongrye Jeon and Freeman, {Burgess B.} and Clay, {Michael R.} and Alberto Pappo and John Easton and Sheila Shurtleff and Anang Shelat and Xin Zhou and Kristy Boggs and Heather Mulder and Donald Yergeau and Armita Bahrami and Mardis, {Elaine R.} and Wilson, {Richard K.} and Jinghui Zhang and Junmin Peng and Downing, {James R.} and Dyer, {Michael A.}",
note = "Funding Information: We thank Nisha Badders for editing the manuscript. This work was supported, in part, by Cancer Center Support (CA21765) from the NCI, grants to M.A.D. from the NIH (EY014867 and EY018599 and CA168875) and ALSAC. M.A.D. was also supported by the Alex's Lemonade Stand Foundation for Childhood Cancer, the Tully Family Foundation, and the Peterson Foundation. E.S. was supported by the National Comprehensive Cancer Network and the National Pediatric Cancer Foundation and is a St. Baldrick's Foundation Scholar with generous support from the Invictus Fund. J.P. is supported by funding from the NIH (AG047928). The majority of this research was supported by the Howard Hughes Medical Institute. Whole-genome sequencing, WGBS, and RNA-seq were performed as part of the St. Jude Children's Research Hospital/Washington University Pediatric Cancer Genome Project. Preclinical studies were performed with assistance from the Animal Imaging Shared Resource; electron microscopy was performed with assistance from the Cell and Tissue Imaging Shared Resource; pharmacokinetics was performed with assistance from the Preclinical Pharmacokinetics Shared Resource; MS was performed in the Proteomics Shared Resource; and histopathologic analysis was performed with assistance from the Veterinary Pathology Shared Resource at St. Jude. Funding Information: We thank Nisha Badders for editing the manuscript. This work was supported, in part, by Cancer Center Support ( CA21765 ) from the NCI , grants to M.A.D. from the NIH ( EY014867 and EY018599 and CA168875 ) and ALSAC . M.A.D. was also supported by the Alex{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer , the Tully Family Foundation , and the Peterson Foundation . E.S. was supported by the National Comprehensive Cancer Network and the National Pediatric Cancer Foundation and is a St. Baldrick's Foundation Scholar with generous support from the Invictus Fund. J.P. is supported by funding from the NIH ( AG047928 ). The majority of this research was supported by the Howard Hughes Medical Institute . Whole-genome sequencing, WGBS, and RNA-seq were performed as part of the St. Jude Children's Research Hospital/Washington University Pediatric Cancer Genome Project. Preclinical studies were performed with assistance from the Animal Imaging Shared Resource; electron microscopy was performed with assistance from the Cell and Tissue Imaging Shared Resource; pharmacokinetics was performed with assistance from the Preclinical Pharmacokinetics Shared Resource; MS was performed in the Proteomics Shared Resource; and histopathologic analysis was performed with assistance from the Veterinary Pathology Shared Resource at St. Jude. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "10",
doi = "10.1016/j.ccell.2018.07.012",
language = "English (US)",
volume = "34",
pages = "411--426.e19",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}