In Silico and in Vitro Drug Screening Identifies New Therapeutic Approaches for Ewing Sarcoma

Oncotarget. 2017 Jan 17;8(3):4079-4095. doi: 10.18632/oncotarget.13385.

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.

Keywords: Ewing sarcoma; auranofin; drug repurposing; ganetespib; high-throughput screening.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Auranofin / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Computer Simulation
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • In Vitro Techniques
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogene Protein c-fli-1 / genetics
  • RNA-Binding Protein EWS / genetics
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / genetics*
  • Transcription Factors / genetics
  • Triazoles / pharmacology*

Substances

  • EWS-ERG fusion protein, human
  • EWS-FLI fusion protein
  • EWS1-WT1 fusion protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • STA 9090
  • Transcription Factors
  • Triazoles
  • Auranofin