21 results on '"Cécile Laurent"'
Search Results
2. Abstract P4-08-25: Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris
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Leonie J. M. J. Delahaye, Liesbet Vliegen, P Sintubin, Laurence Slembrouck, E Van Nieuwenhuysen, I. Vanden Bempt, C Helsmoortel, L Darrigues, S Vander Borght, EL Faron, Cécile Reyes, Sileny Han, H. Wildiers, Lynn Jongen, G Hoste, Annuska M. Glas, Patrick Neven, S Neijenhuis, V Raynal, L. Mittempergher, Anne Vincent Salomon, A Smeets, K Punie, Guiseppe Floris, Anke T. Witteveen, Mylène Bohec, Timothé Cynober, F Reyal, Ines Nevelsteen, Audrey Rapinat, and Cécile Laurent
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Concordance ,Cancer ,medicine.disease ,Beta testing ,University hospital ,Subtyping ,Breast cancer ,MammaPrint ,Internal medicine ,Invasive lobular carcinoma ,medicine ,business - Abstract
Background Many countries restrict patient material exchange to central diagnostic laboratories abroad, limiting access to assays like MammaPrint® (MP) and BluePrint® (BP). Both assays are microarray-based, with MP being prognostic for distant recurrence and BP for molecular subtyping of breast cancer (Luminal-, HER2-, and Basal-type). To increase accessibility, decentralization is required with Next Generation Sequencing (NGS) being the preferred testing platform given that most diagnostic laboratories have the technology in place. The aim of this beta testing study is to validate a previously developed and centrally validated MP and BP NGS kit for RNA samples in two large tertiary academic hospitals in Europe. Patients and Methods Patients with early breast cancer diagnosed at the Multidisciplinary Breast Center at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Patients with bilateral breast cancer or presenting with more than 3 positive lymph nodes were excluded. Only patients with invasive ductal and invasive lobular carcinoma were included. Twenty tissue sections were cut from formalin-fixed, paraffin-embedded (FFPE) blocks; 10 tissue sections were analyzed at the local site using the MP and BP NGS kit, and 10 tissue sections were analyzed at Agendia using the same kit and procedure, as well as with the golden standard method (gene expression microarrays). Targeted RNA sequencing of the 70 MP and 80 BP signature genes was performed on Illumina MiSeq instruments. The raw NGS data generated at the local test sites was sent through a secure file transfer protocol server to Agendia for interpretation and comparison with microarray and NGS performed in the Agendia laboratories. We aimed for a minimum concordance rate between MP and BP outcome of 90% between each local site and Agendia's centralized site. Results In this study, 116 early breast cancer patients were included (73 from University Hospitals Leuven and 43 from Curie Institute). Out of these patients, 52% were MP Low Risk and 48% MP High Risk according to microarray. The patients had a BP luminal, HER2 or basal subtype in respectively 83%, 9% and 8%. Concordance between MP microarray obtained from Agendia and MP NGS obtained from the local sites was 91.4%. Concordance between MP High and Low Risk classification between NGS Leuven versus NGS Agendia was 92.1% and between NGS Curie versus NGS Agendia 95.3%. For BP subtype outcomes, the results from microarray versus NGS for all patients combined from both local sites gave a 98.3% concordance and NGS Agendia versus NGS from each local site gave a 100% concordance. Conclusion The MP and BP NGS kit was successfully validated in a decentralized setting, showing high concordance between results obtained at three different sites. There was a clear benefit of having well-trained NGS experienced diagnostic technical teams. The MP and BP NGS kit the first FFPE targeted RNA sequencing based multigene signature for breast cancer care, will provide a high and equal standard of MP and BP gene expression testing for breast cancer in a decentralized setting. Citation Format: Slembrouck L, Laurent C, Delahaye LJ, Mittempergher L, Vanden Bempt I, Vander Borght S, Darrigues L, Vliegen L, Sintubin P, Raynal V, Bohec M, Reyes C, Rapinat A, Helsmoortel C, Jongen L, Hoste G, Neven P, Wildiers H, Smeets A, Nevelsteen I, Punie K, Van Nieuwenhuysen E, Han S, Salomon AV, Faron EL, Cynober T, Witteveen AT, Neijenhuis S, Glas AM, Reyal F, Floris G. Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-25.
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- 2019
3. Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype
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Julie Bruneau, Véronique Avettand-Fenoel, Ludovic Lhermitte, Morgane Cheminant, Felipe Suarez, Keith Durkin, Maria Artesi, Ambroise Marçais, Olivier Hermine, David Sibon, Vahid Asnafi, Cécile Laurent, Michel Georges, Nicolas Rosewick, Anne Van den Broeke, Claudine Pique, Vincent Hahaut, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Inserm U1016, Institut Cochin, Paris, France, 22 Rue Méchain, 75014 Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Sorbonne-Paris-Cité, Paris, France, Laboratoire de Recherche d'Hémobiologie Cochin, Hôpital Cochin, Paris, France.
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0301 basic medicine ,Cancer Research ,Mutation ,[SDV]Life Sciences [q-bio] ,Hematology ,Biology ,medicine.disease_cause ,medicine.disease ,Somatic evolution in cancer ,Adult T-cell leukemia/lymphoma ,Deep sequencing ,3. Good health ,Lymphoma ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Allele ,Clone (B-cell biology) ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; Adult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation.
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- 2020
4. Medullary Breast Carcinoma, a Triple-Negative Breast Cancer Associated with BCLG Overexpression
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Elisabetta Marangoni, Elodie Manié, Nadège Gruel, Gaëtan MacGrogan, Ivan Bièche, Laetitia Fuhrmann, Cécile Laurent, Dominique Stoppa-Lyonnet, Marc-Henri Stern, Roman Rouzier, Caterina Marchiò, Jaydutt Bhalshankar, Pierre Romero, Sophie Vacher, Gabrielle Deniziaut, Fabien Reyal, Frédérique Berger, Tatiana Popova, Anne Vincent-Salomon, Vanessa Benhamo, and Olivier Delattre
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0301 basic medicine ,Ubiquitin-Protein Ligases ,medicine.medical_treatment ,Triple-Negative Breast Cancer ,Loss of Heterozygosity ,Triple Negative Breast Neoplasms ,Biology ,Pathology and Forensic Medicine ,Targeted therapy ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Medullary breast carcinoma ,polycyclic compounds ,Carcinoma ,medicine ,Humans ,RNA, Neoplasm ,skin and connective tissue diseases ,neoplasms ,Medullary breast carcinoma, Triple-Negative Breast Cancer, BCLG overexpression ,Triple-negative breast cancer ,Retrospective Studies ,BRCA2 Protein ,BCLG overexpression ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,DNA, Neoplasm ,bacterial infections and mycoses ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Carcinoma, Medullary ,030220 oncology & carcinogenesis ,Cancer research ,bacteria ,Immunohistochemistry ,Female ,Genes, Neoplasm - Abstract
Medullary breast carcinoma (MBC) is a rare subtype of triple-negative breast cancer with specific genomic features within the spectrum of basal-like carcinoma (BLC). In this study of 19 MBCs and 36 non-MBC BLCs, we refined the transcriptomic and genomic knowledge about this entity. Unsupervised and supervised analysis of transcriptomic profiles confirmed that MBC clearly differs from non-MBC BLC, with 92 genes overexpressed and 154 genes underexpressed in MBC compared with non-MBC BLC. Immunity-related pathways are the most differentially represented pathways in MBC compared with non-MBC BLC. The proapoptotic gene BCLG (official name BCL2L14) is by far the most intensely overexpressed gene in MBC. A quantitative RT-PCR validation study conducted in 526 breast tumors corresponding to all molecular subtypes documented the specificity of BCLG overexpression in MBC, which was confirmed at the protein level by immunohistochemistry. We also found that most MBCs belong to the immunomodulatory triple-negative breast cancer subtype. Using pan-genomic analysis, it was found that MBC harbors more losses of heterozygosity than non-MBC BLC. These observations corroborate the notion that MBC remains a distinct entity that could benefit from specific treatment strategies (such as deescalation or targeted therapy) adapted to this rare tumor type.
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- 2018
5. Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2
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Océane Anezo, Laura Duciel, Koushik Mandal, David Gentien, Simon Saule, Nathalie Planque, Frédéric M. Coquelle, Jean-Baptiste Manneville, Cécile Laurent, Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Translational Research, Institut Curie [Paris], and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Uveal Neoplasms ,Phosphatase ,lcsh:Medicine ,Nerve Tissue Proteins ,Protein tyrosine phosphatase ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Microfilament ,Article ,Dephosphorylation ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Movement ,Loss of Function Mutation ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,lcsh:Science ,Melanoma ,ComputingMilieux_MISCELLANEOUS ,Multidisciplinary ,Chemistry ,lcsh:R ,medicine.disease ,In vitro ,Neoplasm Proteins ,Actin Cytoskeleton ,030104 developmental biology ,Cytoplasm ,Cancer research ,Intercellular Signaling Peptides and Proteins ,lcsh:Q ,Protein Tyrosine Phosphatases ,030217 neurology & neurosurgery - Abstract
Uveal melanoma (UM) is an aggressive tumor in which approximately 50% of patients develop metastasis. Expression of the PTP4A3 gene, encoding a phosphatase, is predictive of poor patient survival. PTP4A3 expression in UM cells increases their migration in vitro and invasiveness in vivo. Here, we show that CRMP2 is mostly dephosphorylated on T514 in PTP4A3 expressing cells. We also demonstrate that inhibition of CRMP2 expression in UM cells expressing PTP4A3 increases their migration in vitro and invasiveness in vivo. This phenotype is accompanied by modifications of the actin microfilament network, with shortened filaments, whereas cells with a inactive mutant of the phosphatase do not show the same behavior. In addition, we showed that the cell cytoplasm becomes stiffer when CRMP2 is downregulated or PTP4A3 is expressed. Our results suggest that PTP4A3 acts upstream of CRMP2 in UM cells to enhance their migration and invasiveness and that a low level of CRMP2 in tumors is predictive of poor patient survival.
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- 2019
6. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL
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Luc Xerri, Alina Nicolae, Reda Bouabdallah, Joan Somja, Marie-Pierre Chenard, François-Xavier Frenois, Fabien Reyal, Catherine Chassagne-Clément, Lénaïg Mescam, Marie-Hélène Delfau-Larue, Frédéric Escudié, Anne Moreau, Corinne Haioun, Philippe Gaulard, Lucie Oberic, Nadia Amara, Asma Beldi-Ferchiou, Laetitia Lacroix, Alexandra Traverse-Glehen, François Lemonnier, Jean-Marc Schiano, Bruno Tesson, Virginie Fataccioli, Marie Bannier, Daniel Birnbaum, Cécile Laurent, Nadine Martin, P. Brousset, Fabien Le Bras, José Adélaïde, Marc André, Naïs Prade, Camille Laurent, Arnaud Guille, Anne-Sophie Hamy, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Bidaut, Ghislain, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Rt2 Lab, Institut Curie [Paris], CHU Henri Mondor, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Islamic University of Gaza (IUG - IU Gaza), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Carnot Lymphome (CALYM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Groupe de Recherche d'Histoire (GRHis), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'Études des Phénomènes Aléatoires et Géophysiques (CEPHAG), École Nationale Supérieure d'Ingénieurs Électriciens de Grenoble (ENSIEG)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre des maladies du sein, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Surgery Department, CRLCC Paul Strauss, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Henri Mondor, Service d'Hématologie, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IUCT Oncopole - Institut Universitaire du Cancer de Toulouse, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], CHU Henri Mondor [Créteil], École Pratique des Hautes Études (EPHE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut Carnot CALYM [Pierre-Benite], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
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Adult ,0301 basic medicine ,DNA Copy Number Variations ,Breast Implants ,[SDV]Life Sciences [q-bio] ,Immunology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,medicine.disease_cause ,Biochemistry ,Germline ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Epigenetics ,SOCS3 ,STAT3 ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Anaplastic large-cell lymphoma ,PI3K/AKT/mTOR pathway ,ComputingMilieux_MISCELLANEOUS ,Aged ,Janus Kinases ,Aged, 80 and over ,Mutation ,Lymphoid Neoplasia ,Genome, Human ,JAK-STAT signaling pathway ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,[SDV] Life Sciences [q-bio] ,STAT Transcription Factors ,030104 developmental biology ,Cancer research ,biology.protein ,Lymphoma, Large-Cell, Anaplastic ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Signal Transduction ,030215 immunology - Abstract
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
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- 2019
7. A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer
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Cécile Laurent, Gaëlle Pierron, Marion Lavigne, Pierre Painsec, Ivan Bièche, Elisabetta Marangoni, Cécile Reyes, Ahmed Dahmani, Bérengère Ouine, David Gentien, Leanne De Koning, Laura Sourd, Elodie Montaudon, Anne Vincent-Salomon, Ludivine Morisset, Florence Coussy, Samia Melaabi, Franck Assayag, Thibaut Larcher, Sylvain Baulande, Elodie Girard, Céline Callens, Léa Huguet, Sophie Chateau-Joubert, Virginie Bernard, Véronique Diéras, Jean-Luc Servely, Rania El Botty, Anais Boulai, Sophie Vacher, Institut Curie, Institut Curie Research Center (Laboratory of Preclinical Investigation, Department of Translational Research), Translational Research Department, RPPA Platform, Institut Curie Research Center, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Unit of Pharmacogenomics, Department of Genetics, Laboratory of Preclinical Investigation, Department of Translational Research, aboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Translational Research Department, Genomics Platform, U900, Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Somatic Genomics, Department of Genetics, Rt2 Lab, Genomics of Excellence (ICGex) Platform, Institut Curie Research, Department of Medical Oncology, Humanitas Centro Catanese di Oncologia, Inserm U1016, Paris Descartes University, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Neuroblastoma RAS viral oncogene homolog ,endocrine system ,Cancer Research ,Combination therapy ,Class I Phosphatidylinositol 3-Kinases ,[SDV]Life Sciences [q-bio] ,Gene Dosage ,Triple Negative Breast Neoplasms ,Biology ,GTP Phosphohydrolases ,Genetic Heterogeneity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,Animals ,Humans ,Gene Regulatory Networks ,Molecular Targeted Therapy ,Precision Medicine ,Biomarker discovery ,skin and connective tissue diseases ,Gene ,PI3K/AKT/mTOR pathway ,Triple-negative breast cancer ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,Middle Aged ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Female ,Tumor Suppressor Protein p53 ,Neoplasm Transplantation ,Signal Transduction - Abstract
Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.
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- 2019
8. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
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Fariba Nemati, Leanne De Koning, Andrew Wylie, Sophie Piperno-Neumann, Nathalie Cassoux, Sergio Roman-Roman, Didier Decaudin, Cécile Laurent, Ahmed Dahmani, Sébastien Jeay, Estelle Frisch-Dit-Leitz, Chloé Raymondie, Marie Schoumacher, Caroline Emery, Ensar Halilovic, and Guillaume Carita
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Uveal Neoplasms ,0301 basic medicine ,AEB071 combinations ,synergy ,Uveal Neoplasm ,Translational research ,Mechanistic Target of Rapamycin Complex 1 ,Piperazines ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Pyrroles ,Everolimus ,Enzyme Inhibitors ,Melanoma ,Protein Kinase C ,Protein kinase C ,GNA11 ,business.industry ,Cancer ,Proto-Oncogene Proteins c-mdm2 ,Isoquinolines ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Quinazolines ,Cancer research ,xenograft models ,cellular response to anticancer drugs ,Tumor Suppressor Protein p53 ,uveal melanoma ,business ,GNAQ ,Priority Research Paper ,medicine.drug - Abstract
// Guillaume Carita 1,* , Estelle Frisch-Dit-Leitz 2,* , Ahmed Dahmani 1 , Chloe Raymondie 1 , Nathalie Cassoux 3 , Sophie Piperno-Neumann 4 , Fariba Nemati 1 , Cecile Laurent 5 , Leanne De Koning 6 , Ensar Halilovic 7 , Sebastien Jeay 7 , Andrew Wylie 7 , Caroline Emery 7 , Sergio Roman-Roman 2 , Marie Schoumacher 2,* and Didier Decaudin 1,4,* 1 Laboratory of preclinical investigation, Department of Translational Research, PSL University, Institut Curie, Paris, France 2 Department of Translational Research, Institut Curie, PSL University, Paris, France 3 Department of Ophthalmological Oncology, Institut Curie, Paris, France 4 Department of Medical Oncology, Institut Curie, Paris, France 5 Residual Tumor & Response to Treatment Lab, Department of Translational Research, Institut Curie, PSL University, Paris, Paris, France 6 RPPA Platform, Department of Translational Research, Institut Curie, PSL University, Paris, France 7 Novartis Institutes for Biomedical Research, Cambridge, MA USA * These authors have contributed equally to this work Correspondence to: Didier Decaudin, email: // Keywords : xenograft models, cellular response to anticancer drugs, uveal melanoma, AEB071 combinations, synergy Received : April 04, 2016 Accepted : May 10, 2016 Published : May 22, 2016 Abstract Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients.
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- 2016
9. Capecitabine efficacy is correlated with TYMP and RB1 expression in PDX established from triple-negative breast cancers
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Fabien Reyal, Ludmilla de Plater, David Gentien, Justine Fleury, Rania El-Botty, Cécile Laurent, Franck Assayag, Elisabetta Marangoni, Fariba Nemati, Sophie Château-Joubert, Sergio Roman-Roman, Ivan Bièche, Audrey Rapinat, Anne Vincent-Salomon, Jean-Luc Servely, Marick Laé, Nor Eddine Sounni, Ahmed Dahmani, Agnès Noël, Pierre Foidart, Elodie Montaudon, Didier Decaudin, Martine Piccart, Florence Coussy, Sophie Vacher, Translational Research Department, Institut Curie, Université Paris sciences et lettres (PSL), Institut Curie [Paris], BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université de Liège, Department of Pathology, Université libre de Bruxelles (ULB), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche Contre le Cancer (ARC), Parisian Alliance of Cancer Research Institutes (PACRI), Agence Nationale de la Recherche ('Investissements d'Avenir' program) [ANR-10-EQPX-03, ANR-10-INBS-09-08], Canceropole Ile-de-France, SiRIC-Curie program-SiRIC Grant [INCa-DGOS-4654], ProdInra, Migration, École nationale vétérinaire - Alfort (ENVA), and École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)
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0301 basic medicine ,Cancer Research ,Antimetabolites, Antineoplastic ,endocrine system ,medicine.medical_treatment ,Ubiquitin-Protein Ligases ,Context (language use) ,Triple Negative Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Thymidylate synthase ,digestive system ,Capecitabine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Medicine ,Neoplasm ,Animals ,Humans ,Gene Silencing ,RNA, Small Interfering ,Cell Proliferation ,Chemotherapy ,Thymidine Phosphorylase ,biology ,business.industry ,Gene Expression Profiling ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Disease Models, Animal ,Retinoblastoma Binding Proteins ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Immunohistochemistry ,Female ,Fluorouracil ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Purpose: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605–15. ©2018 AACR.
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- 2018
10. Patient-derived xenografts recapitulate molecular features of human uveal melanomas
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David Gentien, Sergio Roman-Roman, Jérôme Couturier, Leanne De Koning, Philippe Hupé, Sophie Piperno-Neumann, Cécile Laurent, Didier Decaudin, Xavier Sastre-Garau, Emmanuel Barillot, Fariba Nemati, Simon Saule, Marc-Henri Stern, Pascale Mariani, André Nicolas, Thierry Dubois, Audrey Rapinat, Bruno Tesson, J. William Harbour, and Laurence Desjardins
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Proto-Oncogene Proteins B-raf ,Uveal Neoplasms ,Cancer Research ,MAP Kinase Signaling System ,DNA Mutational Analysis ,medicine.disease_cause ,Mice ,In vivo ,Tumor Cells, Cultured ,Genetics ,GNAS complex locus ,medicine ,Animals ,Humans ,Melanoma ,Oligonucleotide Array Sequence Analysis ,BAP1 ,Mutation ,GNA11 ,biology ,Tumor Suppressor Proteins ,General Medicine ,medicine.disease ,GTP-Binding Protein alpha Subunits ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Oncology ,Papers ,biology.protein ,Cancer research ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Heterografts ,Molecular Medicine ,Transcriptome ,Ubiquitin Thiolesterase ,GNAQ - Abstract
We have previously developed a new method for the development and maintenance of uveal melanoma (UM) xenografts in immunodeficient mice. Here, we compare the genetic profiles of the primary tumors to their corresponding xenografts that have been passaged over time. The study included sixteen primary UMs and corresponding xenografts at very early (P1), early (P4), and late (P9) in vivo passages. The tumors were analyzed for mutation status of GNAQ, GNA11, GNAS, GNA15, BAP1, and BRAF, chromosomal copy number alterations using Affymetrix GeneChip(®) Genome-Wide Human SNP6.0 arrays, gene expression profiles using GeneChip(®) Human Exon 1.0 ST arrays, BAP1 mRNA and protein expression, and MAPK pathway status using Reverse Phase Protein Arrays (RPPA). The UM xenografts accurately recapitulated the genetic features of primary human UMs and they exhibited genetic stability over the course of their in vivo maintenance. Our technique for establishing and maintaining primary UMs as xenograft tumors in immunodeficient mice exhibit a high degree of genetic conservation between the primary tumors and the xenograft tumors over multiple passages in vivo. These models therefore constitute valuable preclinical tool for drug screening in UM.
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- 2013
11. Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14)
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Nathalie Cassoux, Océane Anezo, Nathalie Planque, Cécile Laurent, S Saule, Sophie Piperno-Neumann, Selma Maacha, Malika Foy, Laurence Mery, Xavier Sastre-Garau, and Géraldine Liot
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0301 basic medicine ,Uveal Neoplasms ,Phosphatase ,Cell ,Uveal Neoplasm ,Fluorescent Antibody Technique ,Protein tyrosine phosphatase ,Biology ,Cell membrane ,03 medical and health sciences ,Cell Movement ,Cell Line, Tumor ,medicine ,Matrix Metalloproteinase 14 ,Humans ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Uvea ,Melanoma ,Cell Membrane ,Cell migration ,Flow Cytometry ,Neoplasm Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Cancer research ,RNA Interference ,Protein Tyrosine Phosphatases - Abstract
PURPOSE To study PTP4A3 phosphatase and MMP14 metalloprotease synergy in uveal melanoma aggressiveness. METHODS Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated. RESULTS We found that the membrane-anchored MMP14 is enriched at the cell surface of OCM-1 cells, patient-derived xenograft cells, and human primary uveal melanoma tumors expressing PTP4A3. Moreover, we show that PTP4A3 and MMP14 colocalize and that the vesicular trafficking of MMP14 is faster in the presence of active PTP4A3. Finally, we demonstrate that inhibition of MMP14 expression in uveal melanoma cells expressing PTP4A3 impairs their migration in vitro and invasiveness in vivo. CONCLUSIONS Our observations indicate that PTP4A3 increases cell membrane accumulation of MMP14 as a result of increased cellular trafficking of the metalloprotease. We also show that downregulation of MMP14 expression reduced PTP4A3-induced cell migration and invasiveness. Taken together, our findings suggest that PTP4A3-related subcellular localization of MMP14 is an important event in metastasis induction.
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- 2016
12. High PTP4A3 Phosphatase Expression Correlates with Metastatic Risk in Uveal Melanoma Patients
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Jérôme Couturier, Bernard Asselain, Corine Plancher, Jean Paul Thiery, David Gentien, Océane Anezo, Benoit Albaud, Laurence Desjardins, Sergio Roman-Roman, Cécile Laurent, Emmanuel Barillot, Audrey Rapinat, Xavier Sastre-Garau, Philippe Hupé, Fabien Valet, Cécile Reyes, Licia Silveri, Sophie Piperno-Neumann, Nathalie Planque, Selma Maacha, and Simon Saule
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Male ,Uveal Neoplasms ,Cancer Research ,Pathology ,medicine.medical_specialty ,Enucleation ,Gene Expression ,Chick Embryo ,Protein tyrosine phosphatase ,Eye Enucleation ,Metastasis ,Gene expression ,Biomarkers, Tumor ,Animals ,Humans ,Medicine ,Melanoma ,business.industry ,Liver Neoplasms ,Cancer ,Cell migration ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Survival Rate ,Oncology ,Female ,Protein Tyrosine Phosphatases ,business ,Chromosomes, Human, Pair 8 ,Comparative genomic hybridization - Abstract
A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas. Cancer Res; 71(3); 666–74. ©2010 AACR.
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- 2011
13. Abstract 3859: Efficacy of capecitabine in chemoresistant PDX established from triple-negative breast cancers with residual disease after neoadjuvant chemotherapy
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Sophie Vacher, Ludmilla de Plater, Ivan Bièche, Franck Assayag, Florence Coussy, Cécile Laurent, Fabien Reyal, Elisabetta Marangoni, and Rania El Botty
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Disease ,Capecitabine ,Internal medicine ,medicine ,business ,Triple negative ,medicine.drug - Abstract
Background: triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy have a high risk of relapse and poor survival. Conventional treatments for relapsed patients are limited, particularly, because standard chemotherapeutic regimens containing anthracyclines and taxanes have usually already been given in the neoadjuvant settings. Our objectives were 1) to identify efficient chemotherapies in patient-derived xenografts (PDX) established from residual TNBC and 2) to determine feasibility of PDX establishment and drug testing before tumor recurrence in patients. Methods: tumors from 51 patients with residual disease at surgery were transplanted in nude mice. Established TNBC PDX were treated with different chemotherapies used in early stages and metastatic settings: anthracyclines combined to cyclophosphamide (AC), taxanes, platins, capecitabine and gemcitabine. Drug responses in PDX were compared to responses in patients who recurred after surgery and were treated in the metastatic setting. Results: overall tumor take of residual tumors was 40% and 75% for TNBC, with 15/20 PDX established, more than twice the tumor take of treatment naïve TNBC (34%). Median latency time, defined as time from implantation till first tumour growth, was only 60 days and was further reduced to 3-4 weeks during successive tumor passages. On the 8 TNBC PDX evaluated for chemosensitivity, 7 exhibited a multidrug-resistance phenotype with resistance or limited response to AC, taxanes and platins. Capecitabine, a chemotherapy given in the advanced stage as second or third line, was efficient in 5 out of 8 PDX tested with 3 models showing stable disease and 2 models durable tumor regressions. Interestingly, capecitabine efficacy was decreased when xenografts were pre-treated with a first line containing platins, suggesting that in some tumors capecitabine might have superior activity when given in the adjuvant setting or as a first line. In one third of TNBC patients, time to recurrence, comprised between 7 and 12 months after surgery, was compatible with xenograft establishment and drug testing. Conclusions and perspectives: we established a unique panel of PDX models from patients with residual disease after neoadjuvant chemotherapy. These aggressive PDX recapitulate the resistance phenotype of patients’ tumors to treatments given in neo-adjuvant and metastatic settings. We identified capecitabine as efficient first line chemotherapy for residual chemoresistant PDX. In 30% of cases, PDX models could have been used to evaluate chemotherapy responses before tumor recurrence occur in patients. In order to identify predictive biomarkers of capecitabine response, additional experiments are ongoing in 25 supplementary TNBC PDX, established from treatment-naïve patients. Citation Format: Elisabetta Marangoni, Cécile Laurent, Florence Coussy, Rania El Botty, Ludmilla de Plater, Franck Assayag, Sophie Vacher, Ivan Bièche, Fabien Reyal. Efficacy of capecitabine in chemoresistant PDX established from triple-negative breast cancers with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3859. doi:10.1158/1538-7445.AM2017-3859
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- 2017
14. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
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Guillaume Carita, Caroline Emery, Ahmed Dahmani, Cécile Laurent, L. De Koning, Chloé Raymondie, Ensar Halilovic, Sophie Piperno-Neumann, Sébastien Jeay, Estelle Frisch-Dit-Leitz, Andrew Wylie, Fariba Nemati, and Nathalie Cassoux
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0301 basic medicine ,Dual inhibition ,Cancer Research ,business.industry ,Melanoma ,mTORC1 ,medicine.disease ,Bioinformatics ,P53 mdm2 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Protein kinase C - Published
- 2016
15. Genetic analyses of uveal melanoma metastases
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M-H Stern, Laurence Desjardins, Sophie Piperno-Neumann, Sergio Roman-Roman, Pascale Mariani, Simon Saule, Cécile Laurent, Emmanuel Barillot, and Jérôme Couturier
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Monosomy ,Pathology ,medicine.medical_specialty ,Melanoma ,General Medicine ,Biology ,medicine.disease ,Primary tumor ,Metastasis ,Transcriptome ,Ophthalmology ,Chromosome 3 ,Cancer research ,medicine ,Gene ,Comparative genomic hybridization - Abstract
Purpose To identify genes linked to metastasis development in uveal melanoma (UM), transcriptome analysis linked to comparative genomic hybridization was performed with 63 primary tumors and 115 liver metastasis. 9 primary tumors and their matched metastasis (couples) were also analyzed. A biostatistical approach was used to define the genetic prognosis parameters. BAP-1 mutations reported to be frequently present in class 2 UM were investigated. Results Fifteen percent of the metastases were found disomic for the chromosome 3 (suggesting a class1 profile) and the couples were monosomic for chromosome 3 (suggesting a class2 profile). Examination of the genomic imbalances in couples (all with monosomy 3, suggesting a class2 profile) indicated that no major alterations occurred at the metastatic step. Very few genes (30) were found differentially expressed between the primary tumor and the metastasis after removal of liver expressed genes. Conclusion These results suggest that the events leading to the metastasis spreading are already present in the primary tumor.
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- 2012
16. Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors
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Sergio Roman-Roman, Jérôme Couturier, Marie-Hélène Donnadieu, Fariba Nemati, Corine Plancher, Bernard Asselain, Didier Decaudin, Isabelle Peguillet, Delphine Robert, Xavier Sastre-Garau, Laurence Desjardins, Cécile Reyes, Olivier Lantz, Marie-Andrée Bessard, Sophie Piperno-Neumann, Simon Saule, David Gentien, Ahmed Dahmani, Cécile Laurent, Emmanuel Barillot, and Pascale Mariani
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Male ,Uveal Neoplasms ,Cancer Research ,Pathology ,medicine.medical_specialty ,Mice, SCID ,Polymorphism, Single Nucleotide ,Nitrosourea Compounds ,Metastasis ,Mice ,Organophosphorus Compounds ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Temozolomide ,Tumor Cells, Cultured ,Animals ,Humans ,Neoplasm Metastasis ,Melanoma ,In Situ Hybridization, Fluorescence ,Oligonucleotide Array Sequence Analysis ,business.industry ,Gene Expression Profiling ,Cancer ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Tumor antigen ,Transplantation ,Dacarbazine ,Oncology ,Cancer research ,Fotemustine ,Female ,business ,medicine.drug ,Tumor Graft - Abstract
Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice. Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma. Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents. Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352–62. ©2010 AACR.
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- 2010
17. PTP4A3, a Signal Molecule Deregulated in Uveal Melanoma Metastasis
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Cécile Laurent, Emmanuel Barillot, Simon Saule, Jérôme Couturier, Laurence Desjardins, Xavier Sastre-Garau, and Sophie Piperno-Neumann
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Transcriptome ,Cell signaling ,business.industry ,Melanoma ,Cancer research ,Medicine ,Effective treatment ,Disease ,Stage (cooking) ,business ,medicine.disease ,Comparative genomic hybridization ,Metastasis - Abstract
Despite improvements in primary treatment protocols, more than 50% of the patients with uveal melanoma die of late-occurring metastases located in the liver. After diagnosis of metastases the average life expectancy is 6 months and no effective treatment is available at this stage of the disease. Transcriptome analysis linked to comparative genomic hybridization have been used for this particular melanoma to identify a set of genes linked to metastasis that may represent valuable future targets for specific treatments.
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- 2010
18. Abstract 4063: Potential targets of PTP4A3 involved in uveal melanoma migration
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Cécile Laurent, Nathalie Planque, Géraldine Liot, Oceane Anezo, Simon Saule, and Selma Maacha
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Cancer Research ,business.industry ,Melanoma ,Cancer ,Cell migration ,medicine.disease ,Transcriptome ,Small hairpin RNA ,Breast cancer ,Oncology ,Downregulation and upregulation ,Tumor progression ,Immunology ,medicine ,Cancer research ,business - Abstract
Uveal melanoma (UM) is the most frequent eye cancer in the adulthood and it represents 4-5% of all melanomas. Although at diagnosis over 95% of patients have disease limited to the eye, about 50% will develop metastases after a median time of three years. From transcriptomic study, we identified PTP4A3/PRL3 level as an efficient predictor of patient's survival. Overexpression of PTP4A3 in UM OCM-1 increased both cell migration and invasiveness. We then got interested in identifying downstream targets of PTP4A3 and more precisely proteins linked to cytoskeleton. We first highlighted collapsin Response Mediator Protein (CRMP2) by 2-D electrophoresis of phosphorus-enriched UM OCM1 stably-expressing PTP4A3 or an inactive catalytic mutant of PTP4A3 (C104S). CRMP2 was dephosphorylated in presence of PTP4A3. CRMP2 expression in UM is inversely correlated with that of PTP4A3, suggesting an antagonistic role of these proteins in tumor progression. Through the use of shRNA in OCM-1, the downregulation of CRMP2 led to an increase in cell migration of PTP4A3-expressing OCM1. In addition, we focused on ATIP3, a protein encoded by the gene MTUS1, which binds to microtubules. In breast cancer, MTUS1 expression was shown to be downregulated in highly proliferative breast carcinomas of poor clinical outcome. Similarly, our transcriptomic analysis showed that expressions of PTP4A3 and MTUS1 were anti-correlated, suggesting that the reduction of MTUS1 gene and ATIP3 expression in UM would be of bad prognosis. In our OCM1 cells, we demonstrated that ATIP3 overexpression blocks proliferation however effect of ATIP3 overexpression on cell migration still need to be elucidaded.In conclusion, CRMP2 and ATIP3 may play a role in the metastatic process of UM tumors expressing high levels of the phosphatase. Citation Format: Geraldine Liot, Oceane Anezo, Cecile Laurent, Selma Maacha, Nathalie Planque, Simon Saule. Potential targets of PTP4A3 involved in uveal melanoma migration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4063. doi:10.1158/1538-7445.AM2014-4063
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- 2014
19. Abstract A9: Establishment and characterization of residual breast cancer patient-derived xenografts resistant to neo-adjuvant therapy
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Marine Carlus, Fabien Reyal, Dalila Labiod, Hélène Bonsang-Kitzis, Franck Assayag, Ivan Bièche, Sophie Richon, Rana Hatem, Cécile Laurent, Alice Pinheiro, Sophie Chateau-Joubert, Elisabetta Marangoni, and Rania El Botty
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Cancer Research ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Lapatinib ,Metastasis ,Breast cancer ,Oncology ,Docetaxel ,Trastuzumab ,Immunology ,medicine ,Cancer research ,biology.protein ,PTEN ,business ,Neoadjuvant therapy ,medicine.drug - Abstract
Background: In HER2 positive and triple-negative breast cancer subgroups, residual disease after neoadjuvant therapy is associated with higher risk of metastatic recurrence compared to patients achieving a pathological complete response. Residual tumor analysis after neoadjuvant treatment is a major and under-explored field to identify resistance mechanisms. To develop patient-derived xenografts (PDX) of residual breast cancer we started a program of residual tumor engraftment in nude mice, following the same procedures previously published for PDX of human breast cancer (Marangoni et al, 2007 and Reyal et al, 2012). Methods: 26 residual breast tumors and 2 residual metastatic axillary lymph nodes were engrafted in swiss nude mice immediately after surgery. Expression of Ki67, HER2, PTEN, P-AKT, P-S6, MET, RET and KIT were analyzed in xenografts by immunohistochemistry, western blot and RT-PCR analyses. Brain, lungs, liver and bones of xenografts were systematically formalin-fixed to search for human metastasis. The in vivo drug response of established xenografts was determined for the following treatments: adryamicin+cyclophosphamide (AC), docetaxel, capecitabine, cisplatin, irinotecan, everolimus, trastuzumab and lapatinib (for the HER2+ PDX). PDX tumors were additionally mechanically dissociated to establish cell lines. Results: Seven PDX were established (tumor take of 25%), 5 triple-negative and 2 HER2+. Six out of seven PDX were metastatic in the lungs. Two xenografts were established from lymph node metastasis. The in vivo drug responses were concordant with the response to neo-adjuvant treatments in patients. Histological analyses showed that xenografts’ tumors recapitulated the patients’ tumor morphology. Residual tumor xenografts expressed high level of Ki67 protein and tumor latency during the first tumor passages was found to be shorter when compared to tumor latency of non pre-treated breast cancers. In 5/5 triple-negative breast cancer PDX the PTEN protein was lost and the PI3 kinase pathway activated. The mTOR inhibitor Everolimus was tested in 2 triple-negative PDX: one was resistant and one was responding, with a tumor growth inhibition of 80%. Triple-negative PDX show expression of “druggable” tyrosin kinase receptors (MET, RET, KIT) providing relevant models to test new target therapies in these models. One cell line was established from a highly metastatic triple-negative breast cancer xenograft. When re-injected into mice, the cell line was tumorigenic, however the tumor architecture was changed and the xenograft was not metastatic. Conclusions: we have established a panel of metastatic PDX models of breast cancer resistant to neo-adjuvant therapies. These models provide a valuable preclinical tool to investigate mechanisms of resistance to neo-adjuvant treatments and for the preclinical testing of new targeted agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A9. Citation Format: Elisabetta Marangoni, Dalila Labiod, Franck Assayag, Rania El Botty, Rana Hatem, Sophie Richon, Sophie Chateau-Joubert, Marine Carlus, Hélène Bonsang-Kitzis, Alice Pinheiro, Cécile Laurent, Ivan Bièche, Fabien Reyal. Establishment and characterization of residual breast cancer patient-derived xenografts resistant to neo-adjuvant therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A9.
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- 2013
20. Abstract LB-263: Identification of gene-expression modifications related to the tumor engraftment in patient-derived xenograft models of solid tumors
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Philippe Hupé, Pascale Mariani, Laurence Desjardins, David Gentien, Virginie Dangles-Marie, Fabien Reyal, Sergio Roman-Roman, Cécile Laurent, Sophie Piperno-Neumann, Oumou Goundiam, Nathalie Cassoux, Elisabetta Marangoni, Fariba Nemati, Xavier Sastre, and Didier Decaudin
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Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,Gene expression ,medicine ,Cancer research ,Identification (biology) ,In patient ,business ,Surgery - Abstract
Objectives. Establishment of pre-clinical models which reflect molecular alterations of primary tumour is a major goal in cancer research. In order to identify novel therapeutic targets and new treatment, xenografts models are powerful tools to analyse pathways and genes involved in carcinogenesis. The aim of this study is to compare gene expression profilings of 4 cancer types (breast, colon, ovary cancer and uveal melanoma) for which primary tumors (PT) and corresponding xenografts (PTDX) are available. We will highlight differentially expressed gene-sets and pathways involved in stromal environment, cancer cells environment, engraftment process and cancer specific development. In addition, this characterisation was associated to survival analysis in breast cancer. Materials and Methods. Gene expression profiling have been determined using Affymetrix technology. Breast cancer dataset was composed of 8 patient/xenograft paired models corresponding to 16 samples, colon, ovary and uveal melanoma datasets was composed of 24, 11 and 12 paired models respectively. Differential analysis between patients and corresponding xenografts was performed on difference matrix (PTDX-PT). Differentially expressed genes were those with a difference unequal to 0. In order to better identified our gene lists, we analysed large public tumors and cell lines datasets. Results. Comparison between PT and corresponding PTDX identified 150 genes always differentially expressed in the different cancer datasets. A large part are down regulated in PTDX. These genes could be divided into two different environments, immunity on one side and angiogenesis, cellular adhesion and development on the other side. Twenty percent are up-regulated and were mainly associated to cell cycle. A large patient and cell lines collections were used for each cancer type in order to differentiate stromal dependant genes and tumor specific genes. A large part of genes were stromal dependant. However some of them presented same expression between patients and cell lines and are lightly deregulated in mice. Survival and response treatment analysis were performed in breast data. In this cancer, genes related to angiogenesis, cellular adhesion and development were associated to survival. Discussion. This descriptive work based on microarray gene-expression profiling allowed to present common genetic background in four different cancer types and increase knowledge in gene micro-environment in carcinogenesis. This study will then focus on breast cancer and we will characterize patient tumors with high probability to grow into mice in order to concentrate on the response to treatment and improve patient management strategies. Citation Format: Cécile Laurent, Elisabetta Marangoni, Philippe Hupé, Fariba Némati, Nathalie Cassoux, David Gentien, Oumou Goundiam, Virginie Dangles-Marie, Sophie Piperno-Neumann, Pascale Mariani, Didier Decaudin, Laurence Desjardins, Xavier Sastre, Sergio Roman-Roman, Fabien Reyal. Identification of gene-expression modifications related to the tumor engraftment in patient-derived xenograft models of solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-263. doi:10.1158/1538-7445.AM2013-LB-263
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- 2013
21. Abstract B16: Genomic, genetic, and gene expression profile characterization of a panel of primary human uveal melanoma xenografts
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Pascale Mariani, Laurence Desjardins, Sophie Piperno-Neumann, David Gentien, Sergio Roman-Roman, Audrey Rapinat, Caroline Hego, Didier Decaudin, Jérôme Couturier, Simon Saule, Cécile Laurent, Emmanuel Barillot, Fariba Nemati, and Xavier Sastre-Garau
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Cancer Research ,GNA11 ,Melanoma ,Cancer ,Biology ,Gene mutation ,Bioinformatics ,medicine.disease ,Metastasis ,Transplantation ,Oncology ,medicine ,Cancer research ,Kinase activity ,GNAQ - Abstract
Background: Uveal melanoma (UM), which is the most common primary malignancy of the eye in adults, is marked by the occurrence of non resectable liver metastases in about 50% of patients, without any curative treatment. New therapeutic strategies are therefore warranted, and require to be evaluated in relevant and predictive preclinical models in this rare tumor. Primary human cancer xenografts, directly obtained from patient's tumors, constitute such models available for pharmacological assessments. We have developed a panel of 16 UM xenografts obtained from intraocular or metastatic tumor lesions and performed a first comparative characterization with their corresponding patient's tumors (Némati et al, CCR 2010). In this study, we have completed this characterization by the determination of their genomic, genetic, and gene expression profiles. Materials and methods: Sixteen UM xenografts at very early (P1), early (P4), and late (P9) in vivo passages and their corresponding patient's tumors have been included in the study. After extraction, available DNA/RNA tumor samples were hybridized and scanned at the Institut Curie microarray core facility. Affymetrix GeneChip® Genome-Wide Human SNP6.0 arrays and protocols were used for DNAs, and Affymetrix GeneChip® Human Exon 1.0 ST arrays and protocols for RNA. Gene mutations of GNAQ, GNA11, and BRAF were detected on tumors, metastasis, xenografts, and derived cell lines by PCR, de novo sequencing using forward and reverse primers (BigDye v1.1, Life Technologies) and capillary electrophoresis on GNAS and GNA15 were screened on tumors and xenografts when mutation of GNAQ, and GNA11 were not seen. Results: Detection of copy number alterations revealed chromosomal aberrations of high risk data sets, including loss of chromosome 1p (46%), gain of 1q (56%), loss of 3 (73%), gain of 6p (37%), loss of 6q (75%), gain of 8q (80%), and multiple genomic alterations in 31/42 samples (73%). Comparison of patient's tumors and corresponding xenografts showed high similarities, with a total correlation score of 0.89. Among the 22517 studied genes, about 3% were differentially expressed between patient's tumors and their corresponding xenografts, in which 2 thirds due to the loss of the human stroma cells during the in vivo transplantation process. The remaining third is due to genes up-expressed in xenografts and related to mitosis, DNA repair, and kinase activity. No differentially expressed genes were found between xenografts at different passages. Finally, with total concordance between patient's tumors and xenografts, GNAQ, GNA11, and BRAF genes were found to be mutated in 31%, 62%, and 0%, respectively. Conclusion: Genomic, genetic, and gene expression profile characterization of our primary human UM xenografts showed a high conservation of their molecular features during their in vivo transplantation process and in vivo maintain into mice. We therefore consider that they constitute relevant preclinical tools for pharmacological experiments. Reference: 1. Némati et al. Clin Cancer Res 2010;16:2352–2362. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B16.
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- 2011
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