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The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model

  • Takashi Higuchi
  • Kentaro Miyake
  • Norihiko Sugisawa
  • Hiromichi Oshiro
  • Zhiying Zhang
  • Sahar Razmjooei
  • Norio Yamamoto
  • Katsuhiro Hayashi
  • Hiroaki Kimura
  • Shinji Miwa
  • Kentaro Igarashi
  • Michael Bouvet
  • Shree Ram SinghEmail author
  • Hiroyuki TsuchiyaEmail author
  • Robert M. HoffmanEmail author
Original Article
  • 66 Downloads

Abstract

Purpose

Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX).

Methods

Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment.

Results

Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis.

Conclusions

The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

Keywords

Undifferentiated soft-tissue sarcoma Olaratumab Doxorubicin Gemcitabine Docetaxel Patient-derived orthotopic xenograft PDOX 

Notes

Acknowledgements

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest. T.H., K.M., N.S., H.O., Z.Z., S.R., N.Y., K.H., H.K., S.M., K.I., and R.M.H. 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

Written informed consent was obtained from the patient as part of a UCLA Institutional Review Board approved protocol (IRB#10-001857).

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Copyright information

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

Authors and Affiliations

  • Takashi Higuchi
    • 1
    • 2
    • 3
  • Kentaro Miyake
    • 1
    • 2
  • Norihiko Sugisawa
    • 1
    • 2
  • Hiromichi Oshiro
    • 1
    • 2
  • Zhiying Zhang
    • 1
    • 2
  • Sahar Razmjooei
    • 1
  • Norio Yamamoto
    • 3
  • Katsuhiro Hayashi
    • 3
  • Hiroaki Kimura
    • 3
  • Shinji Miwa
    • 3
  • Kentaro Igarashi
    • 3
  • Michael Bouvet
    • 2
  • Shree Ram Singh
    • 4
    Email author
  • Hiroyuki Tsuchiya
    • 3
    Email author
  • Robert M. Hoffman
    • 1
    • 2
    Email author
  1. 1.AntiCancer, Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Orthopedic SurgeryKanazawa UniversityKanazawaJapan
  4. 4.Basic Research LaboratoryNational Cancer InstituteFrederickUSA

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