In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma
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Ziyan Y. Pessetto1, Bin Chen2, Hani Alturkmani1, Stephen Hyter1, Colleen A. Flynn3, Michael Baltezor3, Yan Ma1, Howard G. Rosenthal4, Kathleen A. Neville5, Scott J. Weir4,6,7, Atul J. Butte2, Andrew K. Godwin1,4
1Departments of Pathology and Laboratory Medicine, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
2Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA
3Lead Development Optimization Shared Resource, University of Kansas Cancer Center, Biotechnology Innovation and Optimization Center, Lawrence, KS, USA
4University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA
5Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR, USA
6Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA
7Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA
Andrew K. Godwin, email: [email protected]
Keywords: Ewing sarcoma, drug repurposing, auranofin, ganetespib, high-throughput screening
Received: July 22, 2016 Accepted: October 14, 2016 Published: November 16, 2016
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.
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