ABC transporters of the A subfamily: potential prognostic markers and candidates for antibody selection from phage-display libraries for therapeutic use in Ewing sarcoma

The prognostic value of ABC transporters in Ewing sarcoma is still poorly explored and controversial. We described for the first time the impact of various ABCs on Ewing sarcoma prognosis by assessment of their gene expression in two independent cohorts of patients. Unexpected associations with favourable outcomes were observed for two ABCs of the A-subfamily, ABCA6 and ABCA7, whereas no associations with the canonical multidrug ABC transporters were identified. The ABCs of the A-subfamily are involved in cholesterol/phospholipids transportation and efflux from cells. Our clinical data support the drug-efflux independent contribution to cancer progression of the ABCAs, which has been confirmed in PDX-derived cell lines. The impact of these ABCA transporters on tumor progression seems to be mediated by lowering intracellular cholesterol, supporting the role of these proteins in lipid transport. In addition, the gene expression of ABCA6 and ABCA7 is regulated by transcription factors which control lipid metabolism: ABCA6 was induced by the binding of FoxO1/FoxO3a to its promoter and repressed by IGF1R/Akt signaling, whereas the expression of ABCA7 was regulated by p53. The data point to ABCA6 and ABCA7 as potential prognostic markers in Ewing sarcoma and suggest the IGF1/ABCA/lipid axis as an intriguing therapeutic target. Agonist monoclonal antibodies towards ABCA6/7 or inhibitors of cholesterol biosynthesis, such as statins or aminobiphoshonates, may be investigated as therapeutic options in combination with chemotherapy. Considering that no monoclonal antibodies selectively targeting extracellular domains of ABCA6/7 are available, the second part of the project has been dedicated to the generation of human antibody phage-display libraries as tools for selecting monoclonal antibodies. A novel synthetic human antibody phage-display library has been designed, cloned and characterized. The library takes advantages of the high variability of a designed naïve repertoire to be a useful tool for isolating antibodies towards all potential antigens, including the ABCAs.

Les machines du pouvoir. Technique et politique entre l'Iran sassanide et le califat abbasside

Dans l’Antiquité, la recherche sur la technique permet les premières réalisations de dispositifs ingénieux, tels que des appareils qui accomplissent une série d’actions par le biais de stimulus externes et de mécanismes cachés. Les organismes politiques et religieux saisissent rapidement la puissance communicative de ces machines, en devenant les promoteurs et patrons privilégiés de leur production. L’Empire sassanide (224-650) ne constitue pas une exception. En effet, les souverains perses consacrent, au moins à l’époque tardive, une grande attention à la conception et au déploiement de dispositifs savants. De même, un siècle plus tard, dans le milieu du califat islamique, les Abbassides (750-1258) semblent s’entourer de tels dispositifs. La continuité entre les deux empires dans plusieurs domaines, de la théorie politique à l’administration, est bien connue. Cependant, la question de la réutilisation du patrimoine technique et scientifique ancien, et notamment sassanide, par la cour abbasside, demeure encore largement inexplorée. L’étude d’un corpus de sources, aussi vaste qu’hétérogène, rassemblant des ouvrages historiographiques, géographiques, poétiques et d’adab, ainsi que des traités scientifiques et techniques en plusieurs langues, permet d’analyser différents aspects de la production et de l’usage politique des machines. Au sein de la cour sassanide, comme de la cour abbasside, la machine s’avère constituer un véhicule préférentiel de représentation et de diffusion de l’idéologie politique. À travers sa mise en scène publique, elle contribue de manière substantielle à la définition de l’espace du pouvoir, en participant à la création d’une image de la cour comme un microcosme au cœur duquel le Roi des rois, et plus tard le calife, occupaient le rôle cardinal de maître incontesté du monde. La continuité entre les empires sassanide et abbasside dans le domaine technique ne se limite donc pas à une récupération de savoirs, mais s’opère aussi sous la forme d’une véritable réactivation d’un patrimoine symbolique

Molecular engineering of the m13 phage for targeted photodynamic cancer treatment

This thesis explores the advancement of cancer treatment through targeted photodynamic therapy (PDT) using bioengineered phages. It aims to harness the specificity of phages for targeting cancer-related receptors such as EGFR and HER2, which are pivotal in numerous malignancies and associated with poor outcomes. The study commenced with the M13EGFR phage, modified to target EGFR through pIII-displayed EGFR-binding peptides, demonstrating enhanced killing efficiency when conjugated with the Rose Bengal photosensitizer. This phase underscored phages' potential in targeted PDT. A breakthrough was achieved with the development of the M137D12 phage, engineered to display the 7D12 nanobody for precise EGFR targeting, marking a shift from peptide-based to nanobody-based targeting and yielding better specificity and therapeutic results. The translational potential was highlighted through in vitro and in vivo assays employing therapeutic lasers, showing effective, specific cancer cell killing through a necrotic mechanism. Additionally, the research delved into the interaction between the M13CC phage and colon cancer models, demonstrating its ability to penetrate and disrupt cancer spheroids only upon irradiation, indicating a significant advancement in targeting cells within challenging tumor microenvironments. In summary, the thesis provides a thorough examination of the phage platform's efficacy and versatility for targeted PDT. The promising outcomes, especially with the M137D12 phage, and initial findings on a HER2-targeting phage (M13HER2), forecast a promising future for phage-mediated, targeted anticancer strategies employing photosensitizers in PDT.