Combining Tumor-Selective Bacterial Therapy with Salmonella typhimurium A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing's Sarcoma in a Patient-Derived Orthotopic Xenograft Model

Chemotherapy. 2018;63(5):278-283. doi: 10.1159/000495574. Epub 2019 Jan 23.


Background: Ewing's sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics.

Objectives: The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model.

Methods: The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week.

Results: S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p < 0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032).

Conclusions: The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES.

Keywords: Bacterial therapy; Ewing’s sarcoma; Methioninase; Patient-derived orthotopic xenograft; Patient-derived orthotopic xenograft nude mice; Salmonella typhimurium A1-R; Transformative therapy.

MeSH terms

  • Administration, Oral
  • Animals
  • Antibiotics, Antineoplastic / therapeutic use
  • Body Weight
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Carbon-Sulfur Lyases / genetics
  • Carbon-Sulfur Lyases / metabolism
  • Carbon-Sulfur Lyases / therapeutic use*
  • Disease Models, Animal
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / therapeutic use
  • Salmonella typhimurium / pathogenicity*
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology
  • Transplantation, Heterologous


  • Antibiotics, Antineoplastic
  • Recombinant Proteins
  • Doxorubicin
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase