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Intérêt d'approches théranostatiques ciblant les protéoglycanes de la matrice extracellulaire et l'hypoxie en oncologie

Abstract : Skeletal Chondrosarcomas (S-CHS) and Extraskeletal Myxoid Chondrosarcomas (ESM-CHS) are two tumoral pathologies which differs by their etiologies and their anatomical locations. However, they have a similar microenvironment, with Proteoglycans (PG) and hypoxia. At the present time, there is no specific diagnostic tool for these pathologies, which are both described to be chemo- and radioresistant, making surgery the only effective treatment. Based on these observations, the UMR 1240 IMoST INSERM / UCA develops strategies for addressing diagnostic or therapeutic molecules to the negative charges of PG, thanks to a positively charged quaternary ammonium vector. This strategy has also been combined to the concept of hypoxia-activated prodrug to allow selective activation of the therapeutic agent, within hypoxic tumor areas. The hit prodrug, called ICF05016, has already demonstrated its anti-tumor efficacy on murine model of ESM-CHS developed from the H-EMC-SS human cell line inoculated Subcutaneously (SC). The first objective of this PhD work was to characterize the PG content and the hypoxic status of two models of S-CHS (SWARM, JJ012) as well as the ESM-CHS model inoculated in paratibial location. For this purpose, functional imaging techniques ([99mTc] NTP 15-5, [18F] -FMISO, CEST MRI) were used to quantify PG and hypoxia in three models. The next objective was to determine the anti-tumor efficacy of the ICF05016 prodrug on these CHS models. A tumor growth inhibition was observed only for the H-EMC-SS model. Transcriptomic and cell cycle studies had suggested a more in-depth characterization of the comparative physiopathology of S-CHS and ESM-CHS, to be able to develop more specific theranostic strategies. The last objective was to determine the potential of the combination between the ICF05016 prodrug with external beam radiotherapy respectively to radiotherapy alone, on the ESM-CHS model, developed in SC. After determining the radiosensitivity of the H-EMC-SS human cell line, the combination study of the ICF05016 prodrug with external beam radiotherapy (6 Gy) led to an increase in the median survival time of 44 % compared to radiotherapy alone, suggesting the promising future of this prodrug in the medical care of the ESM-CHS.
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Elise Maubert. Intérêt d'approches théranostatiques ciblant les protéoglycanes de la matrice extracellulaire et l'hypoxie en oncologie. Cancer. Université Clermont Auvergne, 2019. Français. ⟨NNT : 2019CLFAS021⟩. ⟨tel-02870914⟩

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