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La caractérisation de la mutation IDH1R¹³²H dans un modèle de gliome humain de haut grade par imagerie multimodale, une étude translationnelle in vitro et in vivo

Abstract : The integration of molecular parameters in the classification of gliomas by the WHO in 2016, particularly IDH1R¹³²H mutational status, has significant diagnostic impact. This mutation is associated with a better prognosis but the physiopathological mechanisms underlying its expression remain poorly understood. Our work evaluates a multimodal imaging approach integrating multiparametric MRI and multiparametric multitracer PET to non-invasively characterize this mutation in gliomas. High grade human glioma cells (U87-MG) expressing or not the IDH1R¹³²H mutation (IDH1+ ; IDH1-), constructed using CRISP/Cas9 were studied in cell culture (in vitro), in a preclinical rat model after stereotactic grafting (in vivo) and after autopsy (ex vivo). In vitro, IDH1+ tumors expressed low levels of integrins αvβ3 and TSPO receptors which are considered to be biological markers of aggressiveness involving angiogenesis and tumor inflammation pathways. In vivo, MRIs (4.7T) of these IDH1+ tumors showed areas of high vascular densities which were characterized by functional neo-vascularizations, comparable to healthy cerebral vascular networks. Magnetic resonance spectra variations confirmed these results and revealed a less aggressive metabolite profile for these IDH1+ tumors. The combination of static and dynamic PET parameters with decreased uptake and a pronounced decrease in the PET slope of [⁶⁸Ga]NODAGA-(RGDyK)₂, as well as decreased PET uptake of [¹⁸F]DPA-714 in IDH1+ tumors, targeting αvβ3 integrins and TSPO receptors, yielded good diagnostic performances to discriminate the IDH1R¹³²H mutation. Ex vivo, spectroscopic analyses indicated less aggressive metabolic profile. This translational study demonstrates the benefits of multimodal and multiparametric imaging, and associates expression of the IDH1R¹³²H mutation, in high-grade human glioma cells with a less aggressive tumor profile. Validation of results from this pilot study in human primary cell cultures, may lead to a clinical multimodal imaging study to non-invasively characterize the IDH1R¹³²H mutation.
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https://hal.univ-lorraine.fr/tel-03230083
Contributor : Thèses Ul <>
Submitted on : Wednesday, May 19, 2021 - 2:53:54 PM
Last modification on : Monday, May 31, 2021 - 8:24:32 AM

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  • HAL Id : tel-03230083, version 1

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Alexandra Clement. La caractérisation de la mutation IDH1R¹³²H dans un modèle de gliome humain de haut grade par imagerie multimodale, une étude translationnelle in vitro et in vivo. Imagerie. Université de Lorraine, 2020. Français. ⟨NNT : 2020LORR0213⟩. ⟨tel-03230083⟩

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