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Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma

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Summary

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 μmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.

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Data availability

The datasets used and/or analysed during this study are available from the corresponding author on request.

Abbreviations

AUC :

Area Under the Curve

EBR :

External Beam Radiotherapy

EMC :

Extraskeletal Myxoid Chondrosarcomas

HAP :

Hypoxia-Activated Prodrug

IV :

Intravenous

SC :

Subcutaneously

SCID :

Severe Combined Immunodeficiency

SD :

Standard Deviation

STS :

Soft Tissue Sarcomas

TGI :

Tumour Growth Inhibition

TSA :

Tyramide Signal Amplification

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Acknowledgements

The authors thank Soubeyrand-Damon Christelle for technical assistance and the ANIPATH platform (UMR 6293 CNRS / U1103 INSERM GReD, Clermont-Ferrand, France) for the immunohistochemical studies.

Funding

The work was supported by the PRT-k Translational Cancer Research INCa-DGOS program (D-TECT project).

Author information

Authors and Affiliations

  1. Clermont Auvergne University, UMR 1240 INSERM IMoST, 58 rue Montalembert, F-63000, Clermont Ferrand, France

    Elise Maubert, Valérie Weber, Aurélien Voissière, Yvain Gérard, Véronique Dedieu, Françoise Degoul, Jean-Michel Chezal, Emmanuel Chautard & Elisabeth Miot-Noirault

  2. Department of Medical Physics, Jean Perrin Comprehensive Cancer Center, F-63000, Clermont Ferrand, France

    Véronique Dedieu

  3. Department of Pathology, Jean Perrin Comprehensive Cancer Center, F-63000, Clermont Ferrand, France

    Emmanuel Chautard

Authors
  1. Elise Maubert
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  2. Valérie Weber
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  3. Aurélien Voissière
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  9. Elisabeth Miot-Noirault
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Contributions

All authors read and approved the manuscript.

Biology experimentations: ME, VA, DV, CE.

Drug synthesis: GY, CJM, WV.

Head of team: DF, MNE.

Methodology: ME, CE, MNE.

Supervision: CE, MNE.

First writing: ME, WV, CE, MNE.

Corresponding author

Correspondence to Elisabeth Miot-Noirault.

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Conflict of interest

Elise Maubert declares that she has no conflict of interest.

Valérie Weber declares that she has no conflict of interest.

Aurélien Voissière declares that he has no conflict of interest.

Yvain Gérard declares that he has no conflict of interest.

Véronique Dedieu declares that she has no conflict of interest.

Françoise Degoul declares that she has no conflict of interest.

Jean-Michel Chezal declares that he has no conflict of interest.

Emmanuel Chautard declares that he has no conflict of interest.

Elisabeth Miot-Noirault declares that she has no conflict of interest.

Ethics approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal studies were carried out in accordance with directive 2010/63/EU after approval by the institutional review board (C2E2A, authorization #9954).

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Maubert, E., Weber, V., Voissière, A. et al. Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma. Invest New Drugs 39, 295–303 (2021). https://doi.org/10.1007/s10637-020-01002-4

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  • DOI: https://doi.org/10.1007/s10637-020-01002-4

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