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Identification et vectorisation de combinaisons de traitements pour la thérapie des tumeurs pulmonaires résistantes aux inhibiteurs de tyrosine kinase de l'EGFR

Abstract : Responsible of 30000 deaths each year in France, lung cancer is a major public health problem. One of the current challenges is to adapt the treatment of lung cancer to offer more effective and less aggressive targeted therapies. EGFR tyrosine kinase inhibitors (EGFR-TKI, gefitinib and erlotinib) represent a real progress in lung cancer therapy. However resistance mechanisms have been described and combination of targeted therapy with EGFR-TKI could overcome resistance in lung cancer.In this context, we studied mechanisms involved in resistance to EGFR-TKI. We show that PI3K/AKT activation is a major pathway leading to EGFR-TKI resistance leading to apoptosis inhibition through acetylation-dependent mechanisms. Histone deacetylase (HADCs) and sirtuin are involved in these mechanisms and modulate PI3K/AKT activation and apoptosis. The use of HDACs inhibitors (HDACi) and sirtuins inhibitors thus restores the sensitivity to EGFR-TKI. Altogether these results confirm the therapeutic effect of the EGFR-TKI/HDACi combination and show the therapeutic potential of the association of EGFR and PI3K/AKT inhibitors to overcome EGFR-TKI resistance.Therapeutic molecules must specifically reach the tumor site, sometimes requiring to protect them against degradation, to reduce their side effects, and to control their release in time and space, using transporters. In the second part of this thesis, we have thus evaluated the lung tumors targeting capabilities of amphiphilic copolymer-based nanoparticles, containing an hydrophilic polysaccharidic block (hyaluronan) and an hydrophobic polypeptidic block (the poly(γ‐benzyl L‐glutamate PBLG). Our work highlights the tumor targeting capability of these nanoparticles injected intravenously, offering new lung cancer therapy perspectives. Our aim is to load the drugs combination (EGFR-TKI/HDACi) in these vectors, to treat the lung tumors resistant to EGFR-TKI.
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https://tel.archives-ouvertes.fr/tel-01684212
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Submitted on : Monday, January 15, 2018 - 12:11:55 PM
Last modification on : Friday, October 23, 2020 - 5:04:16 PM
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  • HAL Id : tel-01684212, version 1

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STAR | U823 | UGA

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Victor Jeannot. Identification et vectorisation de combinaisons de traitements pour la thérapie des tumeurs pulmonaires résistantes aux inhibiteurs de tyrosine kinase de l'EGFR. Biotechnologies. Université Grenoble Alpes, 2015. Français. ⟨NNT : 2015GREAV061⟩. ⟨tel-01684212⟩

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