title: In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma.
abstract: The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches. Among these drugs, 30 were extensively validated as mono-therapeutic agents and 9 in 14 various combinations in vitro. Two drugs, auranofin, a thioredoxin reductase inhibitor, and ganetespib, an HSP90 inhibitor, were predicted to have anti-cancer activities in silico and were confirmed active across a panel of genetically diverse EWS cells. When given in combination, the survival rate in vivo was superior compared to auranofin or ganetespib alone. Importantly, extensive formulations, dose tolerance, and pharmacokinetics studies demonstrated that auranofin requires alternative delivery routes to achieve therapeutically effective levels of the gold compound. These combined screening approaches provide a rapid means to identify new treatment options for patients with a rare and often-fatal disease.
authors.affiliation: Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Ziyan Y
authors.initials: ZY
authors.lastname: Pessetto
authors.affiliation: Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Alturkmani
authors.affiliation: Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.affiliation: Lead Development Optimization Shared Resource, University of Kansas Cancer Center, Biotechnology Innovation and Optimization Center, Lawrence, KS, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Flynn
authors.affiliation: Lead Development Optimization Shared Resource, University of Kansas Cancer Center, Biotechnology Innovation and Optimization Center, Lawrence, KS, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Baltezor
authors.affiliation: Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Howard G
authors.initials: HG
authors.lastname: Rosenthal
authors.affiliation: Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
authors.affiliation: University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA.|Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weir
authors.affiliation: Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.affiliation: Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C450460:EWS-ERG fusion protein, human; C106031:EWS-FLI fusion protein; C106032:EWS1-WT1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C533237:STA 9090; D014157:Transcription Factors; D014230:Triazoles; D001310:Auranofin
keywords: Ewing sarcoma; auranofin; drug repurposing; ganetespib; high-throughput screening