Imatinib revives the therapeutic potential of metformin on ewing sarcoma by attenuating tumor hypoxic response and inhibiting convergent signaling pathways

Cancer Lett. 2020 Jan 28;469:195-206. doi: 10.1016/j.canlet.2019.10.034. Epub 2019 Oct 28.

Abstract

Ewing sarcoma (EwS) is an aggressive pediatric tumor treated with intensive cytotoxic chemotherapies. Overall survival for metastatic or relapsed disease is only 20-30%. Metformin has long been an attractive therapeutic option for EwS, but hypoxia limits its efficacy. Through a systematic integration of drug combination screening, bioinformatics analyses, functional and in vivo studies, and correlation with clinical outcome, we identified another known drug, imatinib that could augment the in vivo anti-tumor capacity of metformin by attenuating tumor hypoxic response. This drug combination regimen widely suppressed multiple dominant mechanisms in EwS genesis, growth, and metastasis, including key EWS-FLI1 downstream targets that converge into the PI3K/AKT/mTOR signaling pathway. In addition, the combination significantly enhanced inhibition on tumor cell proliferation by standard EwS chemotherapy drugs, including cyclophosphamide and ifosfamide. This suggests a potential clinical benefit of the metformin/imatinib combination by allowing the reduction in dose intensity of standard chemotherapy without compromising survival outcome and represents a potential faster track application for EwS patients.

Keywords: Drug combinations; Drug repositioning; Ewing sarcoma; Imatinib; Metformin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Cell Cycle Checkpoints / drug effects
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / genetics
  • Cell Line, Tumor
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Humans
  • Imatinib Mesylate / pharmacology*
  • Imatinib Mesylate / therapeutic use
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Mice
  • Oncogene Proteins, Fusion / metabolism
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / mortality
  • Phosphatidylinositol 3-Kinases / metabolism
  • Progression-Free Survival
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA-Binding Protein EWS / metabolism
  • RNA-Seq
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Imatinib Mesylate
  • Metformin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt