Brain metastases and hypoxia : pre-clinical in vitro and in vivo PET/MRI imaging approaches ; Métastases cérébrales et hypoxie : approches pré-cliniques in vitro et in vivo en imagerie TEP/IRM

Brain metastases (BM) are the most common brain tumors with poor overall survival despite treatments that may be alone or in combination with each other: surgery, radiotherapy (RT) and other treatments depending on those received for the primary cancer. The hypoxic microenvironment contributes, notably through hypoxia-inducible transcription factors (HIF-1 and HIF-2), to tumor growth and resistance to treatments including RT, making hypoxia a poor prognostic factor. The evaluation of hypoxia by biomedical imaging including positron emission tomography (PET) could thus allow a better characterization of the tumor microenvironment for prognostic purposes but also to better guide the therapeutic strategy. The objective of this thesis was to characterize more precisely the tumor microenvironment by multimodal MRI/PET imaging using different radiotracers including 18F-FMISO and 64Cu-ATSM in a preclinical rat model of BM and to evaluate, in vitro, the impact of a HIF-2 inhibition strategy in the same model of BM. We have shown by PET imaging and immunohistological and proteomic analyses that lung cancer-derived BM exhibit a hypoxic microenvironment as well as redox modifications, and this in a more pronounced manner in cortical BM than in striatal BM. The HIF-2 inhibition strategy did not show major results on cell viability, migration or response to RT on lung cancer cells proned to metastasize to the brain. However, this work needs to be complemented by in vivo studies to take in consideration the whole tumor microenvironment. In conclusion, this work highlights that PET imaging with 64Cu-ATSM could be complementary to that with 18F-FMISO and oxygen saturation measured by MRI, notably to adapt treatments such as RT according to the presence or absence of hypoxia or tumor redox modifications. ; Les métastases cérébrales (MC) sont les tumeurs cérébrales les plus fréquentes avec une survie globale qui reste faible malgré les traitements qui peuvent être seuls ou associés les uns aux autres : chirurgie, radiothérapie ...