Auswahl der wissenschaftlichen Literatur zum Thema „Guillaume (14..-1558)“

Abstract Purpose/Objective: There is a need for innovative methods to provide high-quality care to vulnerable populations in an effort to reduce disparities. This is particularly important for women facing a new breast cancer diagnosis. The purpose of the present research was to investigate what social determinants may play a role in the existing disparities impacting adherence to care recommendations in communities with poor access to primary care and higher rates of morbidity and mortality. This study characterized adherence with breast health follow-up care in a diverse population of patients where inequalities exist that may negatively impact adherence to treatment recommendations. The objective of the study was to characterize factors associated with adherence to treatment among women with newly diagnosed breast cancer. Materials/Methods: Women diagnosed with stage I through IV breast cancer treated at the University of Florida College of Medicine-Jacksonville between 01/01/2014 and 12/31/2019 were included in the sample. Patterns of adherence were categorized using machine learning methods with data derived from the electronic medical record and the UF Health Jacksonville Tumor registry. Age, race, and Area Deprivation Index (ADI) state rank in 2019 as a disparity proxy were used to build a machine learning model and classify compliance to treatment. Included patients had a diagnostic procedure that identified breast cancer. Compliance to treatment was fulfilled if the patient received surgery following diagnostic confirmation. A machine learning model was used to stratify patients by risk of non-adherence to treatment following a diagnostic procedure. The models were evaluated using their area under the curve (AUC). Results: A total of 6,951 women were included, 629 who were adherent and 6322 non-adherent patients with breast cancer. The average age of the participants was 61.4 years, (Standard Deviation = 12.8 years). The majority of patients were Black (48%) or Caucasian (45%), 2% were Asian, and 5% were Other races. Payer type at diagnosis showed 45% had Medicare, 30% had commercial insurance, 17% were covered by Medicaid, 7% were charity, and 1% had other sources of pay. Most women were diagnosed with stage III breast cancer. Of 346 patients who received surgery that data was available, 127 (36.7%) had surgery within 30 days of diagnosis, 102 (29.5%) between 31 and 60 days, and 37 (10.7%) between 61 and 90 days. Fifteen models were compared using the PyCaret Python library. The ADI appeared as the most important factor to predict adherence in the model, followed by race and characterized by an AUC of 0.63. Conclusion: Our clinic treats predominantly more women diagnosed with biologically aggressive and advanced breast cancer especially in young African American population. The role social conditions play that precipitate and perpetuate health care disparities were investigated to determine their impact on adherence to treatment. At our safety net hospital, over one third were able to undergo surgery within 30 days of diagnosis. The ADI appeared as the most important feature to predict adherence, followed by race. This demonstrated the necessity to better understand the relation between socio-economical determinants and care received by patients. A more detailed description of the patients’ circumstances, such as access to transport, proximity of the hospital, and insurance status may further improve the model. There is a need for innovative methods of providing quality health care to vulnerable populations. Machine learning models can be used to stratify patients by risk of non-adherence to diagnostic follow-up and treatment following a diagnosis of breast cancer. Future research needs to move from identification of non-adherence risk factors to implementation of interventions to improve breast cancer outcomes. Citation Format: Guillaume Labilloy, Brian Celso, Bharti Jasra, Leigh Neumayer, Erin Mobley, Carmen Smotherman, Jennifer Brailsford. Risk factors for lack of adherence with diagnostic follow-up care in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-14.

Abstract Large chromosomal alterations are common in cancer and often show preferential gain or loss across many cancer types indicating their selective advantage. Triple negative breast cancer (TNBC) exhibits complex mutational spectrum without common oncogenic drivers yet displays consistent loss of large chromosomal regions. Here, we characterize selection pressures that maintain a recurrently deleted region of chromosome 4p in TNBC. We used bulk WGS phylogenetic analysis of TNCB PT/PDX panel to show that chr4p deletion is an early event in tumor evolution. We used scRNAseq gene expression and inferred copy number analysis to show that chr4p loss is associated with a proliferative state. This finding was confirmed by a combination of RNA in situ hybridization and immunofluorescence. We then tested the dosage sensitivity of genes residing within this region by individual and dual overexpression in TNBC PDX-derived cell lines and control normal cell line by assessing their effect on cell proliferation. The overexpression of genes within chr4p elicited a strong cell proliferation defect in cancer but not normal cell line models. We also characterized an unknown gene within chr4p region as a novel member of the STRIPAK complex. Genome-wide pooled ORFeome library screens identified a global pattern of background-specific dosage sensitive regions. Our study shows that large chromosomal deletions are maintained due to evolutionary early genetic network rewiring rendering multiple genes within such regions to be dosage sensitive. Ultimately, this work enhances our understanding of genetic events that modulate TNBC. Citation Format: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Jiannis Ragoussis, Guillaume Bourque, Morag Park. Evolution of large copy number variants in breast cancer through genetic network rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1512.

Abstract Purpose: Immune checkpoint inhibitors (ICI) represent the cornerstone for treatment of patients with metastatic clear-cell renal cell carcinoma (ccRCC). Despite a favourable response for a subset of patients, others present primary progressive disease highlighting the need to better understand plasticity of cancer cells and their crosstalk with the microenvironment to better predict therapeutic response and personalize treatment. Experimental design: We performed single-cell RNA sequencing on 56,421 cells from tumour and normal adjacent tissue of patients with ccRCC at different disease stages. Identification of cancer and microenvironment cell populations was validated by deconvolution analyses of public datasets and their localizations within tumours were determined by spatial transcriptomic analyses. We also assessed association of tumour and microenvironment populations with response of ICI treated patients using data from the BIONIKK clinical trial (NCT02960906). Results: We identify 46 cell populations including 5 tumour subpopulations characterized by distinct transcriptional signatures representing an epithelial to mesenchymal transition gradient as well as novel inflamed state. Deconvolution of the tumour and microenvironment signatures revealed strong correlation between mesenchymal-like ccRCC cancer cells and myofibroblastic cancer-associated fibroblasts (myCAFs) that associate with metastasis and tumour aggressiveness. Spatial transcriptomics revealed their co-localization and we identified therapeutically targetable ligand-receptor interactions underlying their crosstalk. Finally, we show that enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. Conclusions: We describe epithelial-mesenchymal plasticity of ccRCC cancer cells and identify potentially targetable pathways involved in tumour cell-myCAFs crosstalk opening the way for personalized treatment of ccRCC patients. Citation Format: Alexandra Helleux, Guillaume Davidson, Yann A. Vano, Véronique Lindner, Antonin Fattori, Marie Cerciat, Reza T. Elaidi, Virginie Verkarre, Cheng-Ming Sun, Christine Chevreau, Mostefa Bennamoun, Hervé Lang, Thibault Tricard, Wolf H. Fridman, Catherine Sautes-Fridman, Xiaoping Su, Damien Plassard, Céline Keime, Christelle Thibault-Carpentier, Philippe Barthelemy, Stéphane Oudard, Irwin Davidson, Gabriel G. Malouf. Roles of mesenchymal-like tumour cells and myofibroblastic cancer-associated fibroblasts in progression and therapeutic response of clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1342.

Abstract Patients with Lynch Syndrome, an inherited mismatch repair deficiency, have an increased risk for developing microsatellite unstable (MSI-H) cancers. Our team recently identified shared immunogenic frameshift peptides in patient tumors that can be targets of T cell surveillance and preventative MSI-H cancer vaccines. We hypothesize that in Lynch Syndrome some premalignant lesions are capable of evading immune surveillance from cytotoxic T lymphocytes due to immune checkpoint expression and immunosuppression from tumor, myeloid and stromal cell populations. Immune checkpoint blockade (ICB) showed promising results in the treatment of MSI-H tumors and are being evaluated in the adjuvant setting of patients with Lynch syndrome post surgical resection. However, a significant percentage of advanced MSI-H tumors resist ICB suggesting evolving mechanisms of immune resistance. We will use a MSI-H in vivo mouse model and additionally develop 3D spheroids cocultured with immune cells to characterize the underlying immune resistance mechanisms. The MSI-H mouse model will first be applied to identify shared frameshifts in MSI-H tumors by WES to develop vaccination approaches preventing tumor growth. Then, we will quantify MSI-H tumor growth and immune infiltration in the MSI-H mouse model, with or without ICB. We will analyze the presence of immunosuppressive pathways and myeloid subsets in high growth resisting tumors by immunohistochemistry, scRNAseq, spatial transcriptomics and flow cytometry. In addition, we will perform short-term in vitro spheroid-splenic cell co-cultures to better characterize the early immune resistance mechanisms. We will also perform these spheroid-immune cell co-cultures using the immune cells taken from mice after vaccination or ICB to identify the early myeloid immune resistance mechanisms. Overall, the identification of shared immune frameshifts in MSI-H tumors will allow developing peptide vaccination approaches to prevent tumor growth. Further, the identification of myeloid resistance pathways will guide therapeutic strategies against tumor resisting to ICB and/or vaccination. Citation Format: Guillaume Mestrallet. Overcoming immune resistance in DNA mismatch repair deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6652.

Abstract Metastatic relapse after treatment is the primary cause of cancer morbidity and mortality. While genetic mechanisms of primary tumors and, to a lesser extent, metastatic cancers have been studied in large cohorts, refractory metastatic tumors are not yet sufficiently characterized. Markers of aggressiveness and resistance that molecular profiling can extract from these tumors have yet to be identified and incorporated into clinical care. In this study, we present a pan-cancer cohort of 1,031 metastatic tumors (which we refer to as META-PRISM) that are resistant to at least one systemic therapy or with no approved treatment options. We retrieved the complete clinical history of patients and performed whole-exome (n=571) and transcriptome sequencing (n=947) for this cohort. The prevalence of detected cancer biomarkers was assessed and compared to an external cohort of primary tumors. In the META-PRISM cohort, we observed an increase in (i) whole-genome duplication frequency, (ii) tumor mutational burden, (iii) germline cancer-predisposing variants, and (iv) somatic alterations in cancer genes, including KRAS, EGFR, CCND1, MYC, and TP53, as compared to the tumor type-matched primary tumors. The most extensive increase in genomic variation at metastatic stage was observed in prostate cancer. We also identified enrichment of standard-of-care resistance biomarkers in most cancer types. However, only 7.6% of tumors harbored at least one such biomarker, indicating that the current understanding of resistance mechanisms remains insufficient. Our cohort demonstrated a significantly improved 6-month survival prediction from models incorporating molecular markers over models with only clinical markers for breast cancer patients and to a lesser extent for other studied tumor types. Overall, our data establish a unique resource for investigating treatment resistance mechanisms and performing predictive analyses in cancer. Citation Format: Yoann Pradat, Julien Viot, Konstantin Gunbin, Andrei Iurchenko, Marc Deloger, Luigi Cerbone, Guillaume Grisay, Loic Verlingue, Veronique Scott, Stefan Michiels, Antoine Hollebecque, Gerome Jules-Clement, Antoine Laine, Luc Friboulet, Laura Mezquita, Yohann Loriot, Benjamin Besse, Fabrice Andre, Paul-Henry Cournede, Daniel Gautheret, Sergey Nikolaev. Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR009.

Abstract Folate receptor alpha (FOLR1) is a clinically validated target, that is overexpressed extracellularly in numerous solid malignancies with a high unmet medical need. Ovarian, non-small cell lung and breast adenocarcinomas are among indications with the highest frequency of FOLR1-positive patients with one out of two patients showing upregulated topoisomerase I expression. MBK-103, an antibody-drug conjugate targeting FOLR1, is based on Mablink’s novel proprietary hydrophilic drug-linker platform. It is comprised of: (i) an Fc-attenuated humanized IgG1 monoclonal antibody, that selectively binds to FOLR1; (ii) a polysarcosine hydrophobicity masking entity allowing for a high drug-to-antibody ratio (DAR) of 8, while improving the pharmacokinetics and tolerability of the drug; (iii) a proprietary dipeptide cleavable unit and iv) exatecan, a potent topoisomerase I inhibitor. MBK-103 showed excellent ex vivo stability in human plasma enabling a prolonged half-life, similar to that of the unconjugated monoclonal antibody. This led to an increased drug exposure, resulting in a potent antitumor efficacy observed in a collection of more than ten in vivo mouse tumor models with a diverse FOLR1 expression, already at doses as low as 1-3 mg/kg. In addition, the distinct mode of action of exatecan along with the unique characteristics of the proprietary drug-linker platform resulted in the in vivo antitumor potency obtained also in colorectal cancer models, in which tubulin-inhibiting agents exhibit only limited therapeutic effects. The compound was also very well tolerated in cynomolgus monkeys with HNSTD at 50 mg/kg and even when administered repeatedly. High conjugation yields along with 100% homogeneity are major drivers of the successful ongoing manufacturing process with planned IND submission in Q4/2023. Citation Format: Warren Viricel, Louise Conilh, Edouard Leroy, Jean-Guillaume Lafay, Frederique Brune, Lenka Kyrych Sadilkova, Charles Dumontet. MBK-103, a potent novel conjugation platform-based antibody-drug conjugate, changing therapeutic options in folate receptor alpha positive cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1544.

Abstract Background: Over 4,300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for all CAYA with hard-to-cure cancers in Canada. Design: Building upon 3 pre-existing regional precision oncology programs, PROFYLE now includes >20 institutions and has united an interdisciplinary team of experts, leaders, research teams, end-users and advocates from across Canada. The program has 14 domain specific nodes that are unified by a shared governance structure, and has harmonized biobanking, genomics, bioinformatics and reporting procedures. PROFYLE includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples, proteomic analysis, and cancer modelling. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations is provided to the treating oncologist. Results: >1,000 CAYA are included from all of the provinces. Cancer diagnoses: 34% sarcoma, 16% leukemia/lymphoma, 16% CNS tumor, 11% neuroblastoma, 23% other. 17% of participants had a cancer-predisposing pathogenic/likely pathogenic germline variant, 45% had ≥1 potentially actionable somatic alteration, 22.6% had a therapeutically targetable somatic alteration. The most frequent classes of therapeutic alterations were RAS/MAPK (15%), cell cycle (14%), epigenetic (13%), RTK (12%), PI3K/AKT/mTOR (11%), DNA repair (9%), immune checkpoint (8%). Of clinicians who reported the utility of results, 55% indicated the findings were useful for clinical management. Future Directions: Collaborations with other national and international initiatives and data from this interdisciplinary, multi-institutional research program will inform the development of a framework to innovatively link research, clinical and system considerations with Canadian values relevant to multi-omic profiling and drug access for CAYA. In addition, we believe that with a comprehensive molecular view of cancer, PROFYLE will transform our understanding of underlying disease mechanisms, facilitate and improve diagnostic and prognostic indicators, and identify new therapeutic strategies and targets for CAYA patients with cancer. Citation Format: Stephanie A. Grover, Lesleigh Abbott, Jason N. Berman, Guillaume Bourque, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, Conrad V. Fernandez, Cynthia Hawkins, Jan-Willem Henning, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Philipp F. Lange, Paul Moorehead, Michael F. Moran, Daniel A. Morgenstern, Sapna Oberoi, Antonia Palmer, Shahrad R. Rassekh, Donna L. Senger, Adam Shlien, Daniel Sinnett, Caron Strahlendorf, Patrick J. Sullivan, Michael D. Taylor, Suzanne Vercauteren, Anita Villani, Stephanie Villeneuve, James A. Whitlock, David Malkin, on behalf of the PROFYLE Consortium. A pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-cure cancer: The PRecision Oncology For Young peopLE (PROFYLE) Program. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4509.

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It has no approved targeted therapies due to the lack of the expression of key biomarkers, namely Estrogen and Progesterone receptors, and HER2 amplification. As a result, TNBC has the worst prognosis compared to other breast cancer subtypes. We previously showed that chromosome 4p (chr4p) loss is recurrent, correlates with poor prognosis, is an early event in tumor evolution, and confers a proliferative advantage. Here, we propose to leverage chr4p loss as a genetic vulnerability of TNBC by identifying its genetic interactions (GIs) with genes whose inactivation leads to synthetic lethality i.e. loss of viability of chr4p copy loss cells, but not of the chr4p copy neutral cells, or suppression i.e., positive GIs. We first classified breast cancer cell lines with TNBC enriched molecular subtype called basal-like, as chr4p copy loss (9) and chr4p copy neutral (7), using copy number data from CCLE. Associated with chr4p copy loss, the differential expression analysis carried out using CCLE data revealed transcriptomic changes that distinctly cluster the chr4p copy loss and chr4p copy neutral cell lines. We then used the publicly available CRISPR-based genome-wide gene inactivation data from the DepMap project and quantified chr4p loss-associated GIs using multiple scoring methods such as drugZ and MAGeCK. In total, we identified ~200 negative and ~70 positive statistically significant GIs involving genes annotated to biological processes such as translation, metabolism, and others. We have prioritized a subset of them for subsequent experimental validation using CRISPR-Cas9-based gene editing in TNBC cancer cell line models. Alongside, using the publicly available drug sensitivity data obtained from the PRISM project, we identified compounds that impair cell growth in a chr4p loss-specific manner, the strongest of which targeted redox balance. Collectively, the set of GIs, the compound sensitivities, and the computational methods we have generated are unique resources for developing precision oncology therapeutic strategies for TNBC, as well as for other cancers harboring chr4p loss. Citation Format: Rohan Dandage, Michael Schwartz, Lynn Karam, Alain Pacis, Traver Hart, Guillaume Bourque, Morag Park, Elena Kuzmin. Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1413.

Abstract SAR444245 (formerly THOR-707) is a site-specific pegylated recombinant human IL-2 molecule which blocks IL-2R alpha-binding while retains near-native affinity for beta/gamma IL-2 receptor subunits. SAR444245 reduces B16-F10 tumor proliferation in C57BL/6 mice and induces a short transient migration of CD8+ T and NK cells from peripheral blood to lymphoid organs before a strong proliferation (Ptacin et al, Nat Commun 2021). Here we report CD8+ T cells imaging post SAR444245 as monotherapy in naive and tumor bearing mice using nuclear imaging. An anti-murine CD8+ PET probe was injected in mice 24 hours post SAR444245 administration and nuclear imaging was performed at different times over 6 days. In C57BL/6 naive and in poorly immunogenic B16-F10 tumor bearing animals, images reveal a decreased Standardized Uptake Value (SUV) within blood in treated animals at 3mg/kg compared to control ones. In parallel, blood SUV Ratio (SUVR) increases within spleen, lymph nodes and thymus after SAR444245 injection compared to control mice. On tumor site, a stronger SUVR is measured at 144 hours post injection in SAR444245 treated group than in the control group. A dose escalation ranging from 1 to 6 mg/kg of SAR444245 was performed in highly immunogenic CT26 tumor bearing animal. Blood SUV decreases in the treated groups compared to the control group. In lymphoid organs, all SUVR increase at 144 hours post injection in the treated groups compared to the control one. In CT26 tumors, a slight increase of the SUVR is observed for groups treated at 3 and 6 mg/kg. In parallel, a pronounced reduction of tumor growth is observed in the treated group at 6mg/kg. These studies non-invasively confirm the mode of action of SAR444245 with a rapid relocation of CD8+ T cells from peripheral blood to lymphoid organs and tumor site. Citation Format: Sebastion d'Heilly, Fabrice Tirode, Maxime Gaulin, Dudzicki Anne, Guillaume Bluet, Stéphane Guerif, Francis Descamps, Peter Casteels, Xiangming Li, Rui Wang, Robin Meng, Erwan Jouannot. Noninvasive immuno-PET imaging of CD8+T cell behavior in tumor bearing mice models treated with SAR444245. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3580.

Abstract METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p<0.01, relative to vehicle control) inhibited cancer progression as measured by in-life imaging in addition to flow cytometry of hCD45+ cells in bone marrow, blood and spleen; M3i had minimal effects on hematopoiesis in this model with no significant changes in RBCs, WBCs and neutrophils, but an increase in platelets (measured by IDEXX). In an orthotopic, patient-derived xenograft model of AML (LEXF 41283, intratibial implantation, female NSG mice), M3i (30 mg/kg, i.p., QDx91 days) significantly prolonged survival (p<0.01, relative to vehicle control) with a commensurate absence of hCD45+ cells following compound treatment. These results confirm that the pharmacological inhibition of METTL3 is a viable strategy for the treatment of AML and support the additional exploration of the role of METTL3 inhibitors in alternate blood cancers as well as solid tumors. Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6282.

Cette thèse étudie un groupe de familles alliées au XVIe siècle, formant un clan de pouvoir aux vastes dimensions. Guillaume Bochetel, secrétaire d’État de 1547 à sa mort en 1558, est l’architecte de ce clan. Par les alliances nouées pour ses enfants, il a rassemblé autour de lui plusieurs familles de robins en ascension par le service du roi, les L’Aubespine, les Bourdin, les Morvillier notamment qui, à leur tour, ont apporté leurs propres alliés, comme les Neufville ou les Brulart. L’étude est menée du XVe siècle, moment où plusieurs familles se mettent au service des princes dans le Val de Loire, et le début du XVIIe siècle lorsque le clan se délite progressivement, laissant pour héritier politique Villeroy, secrétaire d’État de Charles IX à Louis XIII. Il s’agit de mettre en évidence un groupe de pouvoir particulier, marqué par une forte solidarité, et l’importance des liens du sang, dont les membres exercent les plus hautes charges sous les Valois. Ils détiennent la plupart des secrétariats d’État entre 1547 et 1588 et occupent régulièrement des charges diplomatiques en Europe. Le fonctionnement d’un tel clan, avec ses rivalités, les rôles dévolus à chacun, et ses différentes figures est mis en avant. Le clan, par son ancrage en Berry, où il dispose de nombreux alliés, permet également d’examiner la manière dont se noue le dialogue entre la cour de France et les provinces. Les hommes et les femmes du clan ont en partage une identité sociale particulière, entre haute robe cultivée et noblesse. Ce clan offre ainsi un miroir des transformations de la monarchie française à l’époque moderne, entre État domestique et naissance progressif d’une administration expérimentée
This thesis study a familial group which composes a clan of power whose extension is very large. Guillaume Bochetel, secretary of State between 1547 and his death in 1558, is the architect of this clan. Through the alliances forged for his children he has reunited around him several families of “robins” who move up the social ladder thanks the service of the king, such as the L’Aubespine, the Bourdin or the Morvillier who in turn have brought their own allies, such as the Neufville or the Brulart. The study covers a period between the 15th century, when several families start serving the princes of the Val de Loire and the beginning of the 17th century when the clan is progressively fading away leaving Villeroy as the political heir, secretary of State between Charles IX and Louis XIII. The purpose is to underline a particular group of power marked by a strong solidarity and the importance of blood links, whose members hold the highest offices under the Valois. They possess the majority of the secretaries of State between 1547 and 1588 and are regularly sent as diplomates in Europe. The functioning of this clan with its rivalries, the roles given to each member and its different figures is outlined. The clan, through his allies in Berry, allows to study the dialog between the French court and the provinces. The men and women of this clan share a particular social identity, between the “haute robe” and the nobility. This clan offers also a mirror of the transformations of the French monarchy in the modern era, between a domestic state and the progressive birth of an experimented administration