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

Abstract

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.

Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

“…In addition to more accurately representing the genetics of the primary tumor (at least during early passages) [377], PDXs may more faithfully represent the architecture of the primary tumor and the involvement of non-tumor stroma. PDX models have been established and used for individualized drug sensitivity testing [378][379][380][381][382][383]. To date, PDX models have not been extensively employed for the study of EwS metastasis, though it has been suggested that PDXs, especially when placed orthotopically rather than subcutaneously, may provide a more tractable model of metastasis for a variety of cancer types [384].…”

Over-methylation of Histone H3 Lysines Is a Common Molecular Change Among the Three Major Types of Soft-tissue Sarcoma in Patient-derived Xenograft (PDX) Mouse Models

“…The overmethylation of H3K4me3 and H3K9me3 found in the 3 major types of sarcoma in the present study may be related to methionine addiction, a fundamental hallmark of cancer (24)(25)(26)(27)(28), termed the Hoffman effect (29)(30)(31). The over-methylation of these histone marks required excess methionine in the form of S-adenosylmethionine and may, at least in part, account for the excess methionine required by cancer cells and is a basis why methionine restriction with recombinant methioninase has been an effective therapy for sarcoma in all major types of sarcoma PDOX models (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”

Current Status and Perspectives of Patient-Derived Models for Ewing’s Sarcoma

“…Salmonella typhimurium A1-R is a strain with high tumor colonization and antitumor efficacy [ 91 ]. Miyake et al [ 92 ] demonstrated that combination treatments with rMETase and Salmonella typhimurium A1-R had significantly more prominent antitumor effects in PDOXs of Ewing’s sarcoma, compared with monotherapy with each agen. These reports demonstrated that PDXs and PDOXs can facilitate drug development and serve as tools of pre-clinical study.…”