In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma.
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.
['Pessetto|Ziyan Y|ZY|', 'Chen|Bin|B|', 'Alturkmani|Hani|H|', 'Hyter|Stephen|S|', 'Flynn|Colleen A|CA|', 'Baltezor|Michael|M|', 'Ma|Yan|Y|', 'Rosenthal|Howard G|HG|', 'Neville|Kathleen A|KA|', 'Weir|Scott J|SJ|', 'Butte|Atul J|AJ|', 'Godwin|Andrew K|AK|']
D000971:Antineoplastic Combined Chemotherapy Protocols D001310:Auranofin D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D003198:Computer Simulation D004354:Drug Screening Assays, Antitumor D015972:Gene Expression Regulation, Neoplastic D006801:Humans D066298:In Vitro Techniques D015514:Oncogene Proteins, Fusion D051789:Proto-Oncogene Protein c-fli-1 D034802:RNA-Binding Protein EWS D012512:Sarcoma, Ewing D014157:Transcription Factors D014230:Triazoles
Ewing sarcoma auranofin ganetespib drug repurposing high-throughput screening