Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimenta
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PRECLINICAL STUDIES
Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma Elise Maubert 1 & Valérie Weber 1 & Aurélien Voissière 1 & Yvain Gérard 1 & Véronique Dedieu 1,2 & Françoise Degoul 1 & Jean-Michel Chezal 1 & Emmanuel Chautard 1,3 & Elisabeth Miot-Noirault 1 Received: 17 August 2020 / Accepted: 10 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Human extraskeletal myxoid chondrosarcoma . Hypoxia . External beam radiotherapy . Hypoxia-activated prodrug
Background Extraskeletal Myxoid Chondrosarcoma (EMC) are considered as rare soft tissue sarcomas (STS) [1] characterized by chondroblast-like malignant cells clusters embedded in a glycosaminoglycan matrix with a multinodular growth pattern. EMC occurs at around the age of 50 and men are more affected with a sex-ratio of 2:1 [2, 3]. The primary site of this pathology is usually the limbs but it can also be found in the abdomen, the pelvis and more rarely in some other localizations (orbit, * Elisabeth Miot-Noirault [email protected] 1
Clermont Auvergne University, UMR 1240 INSERM IMoST, 58 rue Montalembert, F-63000 Clermont Ferrand, France
2
Department of Medical Physics, Jean Perrin Comprehensive Cancer Center, F-63000 Clermont Ferrand, France
3
Department of Pathology, Jean Perrin Comprehensive Cancer Center, F-63000 Clermont Ferrand, France
mandible, neck, lung, heart) [4]. EMC has a strong tendency to local recurrence (37–48%) and can metast
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