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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 5, pp 809–815 | Cite as

Regorafenib regressed a doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude mouse model

  • Kentaro Miyake
  • Tasuku Kiyuna
  • Kei Kawaguchi
  • Takashi Higuchi
  • Hiromichi Oshiro
  • Zhiying Zhang
  • Sintawat Wangsiricharoen
  • Sahar Razmjooei
  • Yunfeng Li
  • Scott D. Nelson
  • Takashi Murakami
  • Yukihiko Hiroshima
  • Ryusei Matsuyama
  • Michael Bouvet
  • Sant P. Chawla
  • Shree Ram SinghEmail author
  • Itaru EndoEmail author
  • Robert M. HoffmanEmail author
Original Article

Abstract

Purpose

Ewing’s sarcoma (ES) is a rare and recalcitrant disease which is in need of a development of a novel effective therapy. The aim of this study was to investigate the efficacy of regorafenib on an ES tumor in a patient-derived orthotopic xenograft (PDOX) model.

Methods

The ES PDOX models were established orthotopically in the right chest wall of nude mice to match the site of the tumor in the donor patient. The ES PDOX models were randomized into three groups (G) when the tumor volume reached 75 mm3: G1: untreated control; G2: doxorubicin (DOX) (i.p., 3 mg/kg, weekly, 2 weeks); G3: regorafenib (REG) (p.o., 30 mg/kg, daily, 2 weeks). Tumor volume and body weight were measured twice a week. All mice were sacrificed on day 15.

Results

DOX was ineffective compared to the control group (P = 0.229). REG regressed the tumor size (P < 0.001 and P < 0.001, relative to control and DOX, respectively).

Conclusions

Our findings suggest that REG has clinical potential for ES patients whose tumors respond to REG in a PDOX model.

Keywords

Ewing’s sarcoma Patient-derived orthotopic xenograft PDOX Nude mouse Regorafenib 

Notes

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, M.D., and Sun Lee, M.D.

Funding

This work was supported in part by a Yokohama City University research grant “KAMOME Project” which had no role in the research or writing the paper.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest. K.M., T.K., K.K., T.H., H.O., Z.Z., S.W., S.R., T.M., Y.H., and RMH are or were unsalaried associates of AntiCancer, Inc. AntiCancer, Inc. uses PDOX models for contract research.

Ethical approval

All experiments were performed with an AntiCancer Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study and in accordance with the principals and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1.

Informed consent

The patient signed an informed consent form. This study was approved by the Institutional Review Board of UCLA.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kentaro Miyake
    • 1
    • 2
    • 3
  • Tasuku Kiyuna
    • 1
    • 2
  • Kei Kawaguchi
    • 1
    • 2
  • Takashi Higuchi
    • 1
    • 2
  • Hiromichi Oshiro
    • 1
    • 2
  • Zhiying Zhang
    • 1
    • 2
  • Sintawat Wangsiricharoen
    • 1
  • Sahar Razmjooei
    • 1
    • 2
  • Yunfeng Li
    • 4
  • Scott D. Nelson
    • 4
  • Takashi Murakami
    • 3
  • Yukihiko Hiroshima
    • 3
  • Ryusei Matsuyama
    • 3
  • Michael Bouvet
    • 2
  • Sant P. Chawla
    • 5
  • Shree Ram Singh
    • 6
    Email author
  • Itaru Endo
    • 3
    Email author
  • Robert M. Hoffman
    • 1
    • 2
    Email author
  1. 1.AntiCancer IncSan DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Gastroenterological SurgeryYokohama City University Graduate School of MedicineYokohamaJapan
  4. 4.Department of PathologyUniversity of CaliforniaLos AngelesUSA
  5. 5.Sarcoma Oncology CenterSanta MonicaUSA
  6. 6.Basic Research LaboratoryNational Cancer InstituteFrederickUSA

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