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Analyse Intégrée génomique, protéomique et radiomique des Sarcomes Pléomorphes Indifférenciés : Identification et Validation de nouvelles cibles thérapeutiques

Abstract : Undifferentiated Pleomorphic Sarcoma (UPS) are an heterogeneous group of poorly differentiated tumors made up ‘by default’. We hypothesized that there is a link between dedifferentiation state of UPS and immune infiltrate and that this relation relies on specific pathways activation and related genomics alterations with potential therapeutic impact. Objectives of this work were to generate a comprehensive Omics landscape of UPS, integrating genomic, immuno-phenotypic, proteomic and radiomic approach, and to identify and test potential targets for therapeutic approach on cell lines and patients tumor mouse xenografts (PDX). We analyzed a cohort of 135 UPS samples from patients in our institution, of whom 25 were selected for full exome and RNA-sequencing. Unsupervised consensus and hierarchical clustering of RNA-sequencing identified 3 groups, A, B and C. Group A was mainly enriched in genes that play a crucial role in both normal development and stemcellness, notably LHX8, LRRN1, LGR5, BMP5 and FGFR2. Group B was strongly enriched in genes involved in immunity, including MARCO, TIMD4, TIGIT, CD27, IFNG, CD8B, PDCD1, CD3D and IDO1, but also DKK1. Group C was too small to be analyzed with sufficient robustness. This classification was confirmed on an independent cohort of 41 UPS from TCGA consortium. We found a high correlation between gene expression and protein density by IHC on related tumor sample slides for CD8, PD-1 and IDO1, leading to call group B ‘immune-high’ and group A ‘immune-low’. In an independent validation cohort of 110 UPS patients, CD8 expression was significantly associated with metastase-free survival (p = 0.04). Copy numbers variations were significantly more frequent in the immune-low group. Main recurrent events were deletions, notably in PTEN, RB1, FANCA, FAS, CDKN2A, TP53, AXIN1, NF2 and BRCA2. Proteomic analysis allowed us to detect two main proteomic groups - PA and PB – that highly correlated with the two main transcriptomic groups - A and B. Group PB was significantly enriched in immune response pathways, whereas group PA was enriched in MYC targets and epithelial-mesenchymal transition pathways. We then further developed cell lines and PDX models from patient tumor samples included in the molecular profiling study for each class, A, B, C. We showed robust in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 in cell lines and PDX models from group A, selectively. We also showed in vitro activity of three potent dual inhibitors of BET-proteins CBP/P300, CPI637, NEO1132 and NEO2734, in cell lines from group A, selectively. Finally, we showed that a set of 9 radiomic features from basic MRI conventional sequences correlated well with our UPS molecular classification and provided the basis for a radiomics signature that could select immune-high UPS on their pretherapeutic imaging. This study is the first to give a comprehensive genomic, immuno-phenotypic, proteomic and radiomic landscape of non-pretreated primary UPS. We identified two main groups of UPS with therapeutics potential: the immunehigh group, strongly inflamed and probably the best candidate for immunotherapy, and the immune-low group, with a rational for FGFR and BET inhibitors activity in this one.
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https://tel.archives-ouvertes.fr/tel-02900286
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Maud Toulmonde. Analyse Intégrée génomique, protéomique et radiomique des Sarcomes Pléomorphes Indifférenciés : Identification et Validation de nouvelles cibles thérapeutiques. Médecine humaine et pathologie. Université de Bordeaux, 2019. Français. ⟨NNT : 2019BORD0429⟩. ⟨tel-02900286⟩

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