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1. Polymeric Encapsulation of a Ruthenium(II) Polypyridyl Complex: From Synthesis to in vivo Studies against High-Grade Epithelial Ovarian Cancer

Author

João P. M. António, Albert Gandioso, Fariba Nemati, Nancy Soliman, Robin Vinck, Fan Sun, Carine Robert, Pierre Burckel, Didier Decaudin, Christophe M. Thomas, Gilles Gasser, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche de Chimie Paris (IRCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Institut de Physique du Globe de Paris (IPGP (UMR_7154)), Institut national des sciences de l'Univers (INSU - CNRS)-Université de La Réunion (UR)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ERC, and European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017)

Subjects
General Chemistry, Cancer des ovaires, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Cancer - Thérapeutique, Ruthenium
Abstract

The in vitro to in vivo translation of metal-based cytotoxic drugs has proven to be a significant hurdle in their establishment as effective anti-cancer alternatives. Various nano-delivery systems, such as polymeric nanoparticles, have been explored to address the pharmacokinetic limitations associated with the use of these complexes. However, these systems often suffer from poor stability or involve complex synthetic procedures. To circumvent these problems, we report here a simple, one-pot procedure for the preparation of covalently-attached Ru-polylactide nanoparticles. This methodology relies on the ring-opening polymerization of lactide initiated by a calcium alkoxide derivative formed from calcium bis(trimethylsilyl amide) and a hydroxyl-bearing ruthenium complex. This procedure proceeds with high efficiency (near-quantitative incorporation of Ru in the polymer) and enables the preparation of polymers with varying molecular weights (2000-11000 Da) and high drug loadings (up to 68% w/w). These polymers were formulated as narrowly dispersed nanoparticles (110 nm) that exhibited a slow and predictable release of the ruthenium payload. Unlike standard encapsulation methods routinely used, the release kinetics of these nanoparticles is controlled (no ‘burst released’ was observed) and may be adjusted on demand, by tuning the size of the polymer chain. In terms of cytotoxicity, the nanoparticles were assessed in the ovarian cancer cell line A2780 and displayed potency comparable to cisplatin and the free drug, in the low micromolar range. Interestingly, the activity was maintained when tested in a cisplatin-resistant cell line, suggesting a possible orthogonal mechanism of action. Additionally, the internalization in tumour cells was found to be significantly higher than the free ruthenium complex (> 200 times in some cases), clearly showcasing the added benefit in the drug’s cellular permeation and accumulation of the drug. Finally, the in vivo performance was evaluated for the first time in mice. The experiments showed that the intravenously injected nanoparticles were well tolerated and were able to significantly improve the pharmacokinetics and biodistribution of the parent drug. Not only was the nanosystem able to promote an 18-fold increase in tumour accumulation, but it also allowed a considerable reduction of drug accumulation in vital organs, achieving, for example, reduction levels of 90% and 97% in the brain and lungs respectively. In summary, this simple and efficient one-pot procedure enables the generation of stable and predictable nanoparticles capable of improving the cellular penetration and systemic accumulation of the Ru drug in the tumour. Altogether, these results showcase the potential of covalently-loaded ruthenium polylactide nanoparticles and pave the way for its exploitation and application as a viable tool in the treatment of ovarian cancer.

Published
2022

2. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Author

Zakia Tariq, Sunil Pancholi, Nikiana Simigdala, Thibaut Larcher, Virginie Bernard, Mariana Ferreira Leal, Sophie Château-Joubert, Camilla Rega, Muriel Le Romancer, Fariba Nemati, Didier Decaudin, Ludivine Morisset, Anne Vincent-Salomon, Rania El Botty, Elisabetta Marangoni, Ahmed Dahmani, Cécile Reyes, Walid Chemlali, Audrey Rapinat, Ricardo Ribas, Guillaume Dutertre, Didier Meseure, Lesley-Ann Martin, Paul Cottu, Elodie Montaudon, Julien Masliah-Planchon, Sophie Vacher, Keltouma Driouch, Joanna Nikitorowicz-Buniak, Laura Sourd, Léa Huguet, Florence Coussy, Mylène Bohec, André Nicolas, Sylvain Baulande, Ivan Bièche, Pierre Painsec, David Gentien, Translational Research Department, Institut Curie, PSL Research University, Paris 75248, France, The institute of cancer research [London], Service de génétique, Institut Curie Paris, École nationale vétérinaire d'Alfort (ENVA), Department of pathology, Institut Curie, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Department of Medical Oncology, Institut Curie, Paris 75248, France, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie/ Departement de chirurgie/ 26 rue d'Ulm/ 75005 Paris, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BABARIT, Candice

Subjects
0301 basic medicine, Pyridines, General Physics and Astronomy, Cell Cycle Proteins, 02 engineering and technology, Piperazines, Transcriptome, Mice, Breast cancer, Cyclin D1, lcsh:Science, Exome sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Pteridines, 021001 nanoscience & nanotechnology, Immunohistochemistry, 3. Good health, G2 Phase Cell Cycle Checkpoints, 0210 nano-technology, medicine.drug, DNA Copy Number Variations, Science, Immunoblotting, Anastrozole, Mice, Nude, Breast Neoplasms, Palbociclib, Protein Serine-Threonine Kinases, PLK1, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Targeted therapies, Cell Line, Tumor, Proto-Oncogene Proteins, Exome Sequencing, medicine, Animals, Humans, Immunoprecipitation, Cancer models, neoplasms, Cell growth, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, lcsh:Q, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment., Identifying novel therapies for the treatment of CDK4/6 inhibitor-resistant patients is of great importance. Here, the authors demonstrate that PLK1 inhibition is a potential therapeutic target in CCND1-driven and in RB-positive Palbociclib-resistant breast cancers.

Published
2020

3. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Author

Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genetics Department, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), U830, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), Université de Liège, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, Queen's cancer reserach institute, Queen's University, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), Mines Paris - PSL (École nationale supérieure des mines de Paris), 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), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes

Subjects
Anthracycline, DNA repair, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Triple Negative Breast Neoplasms, Topoisomerase-I Inhibitor, Irinotecan, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, CHEK1, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, biology, Retinoblastoma, business.industry, Topoisomerase, Nuclear Proteins, General Medicine, medicine.disease, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Retinoblastoma Binding Proteins, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Topoisomerase I Inhibitors, business, Schlafen family member 11, medicine.drug
Abstract

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

Published
2020

4. Capecitabine efficacy is correlated with TYMP and RB1 expression in PDX established from triple-negative breast cancers

Author

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)

Subjects
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.

Published
2018

5. The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages

Author

Sergio Roman-Roman, Marie-Aude Le Frère-Belda, Isabelle Navarro-Teulon, Jean-Marc Barret, Houcine Bougherara, Charlotte Ngo, Jean-François Prost, Alexandra Leary, André Nicolas, Jérôme Alexandre, André Pèlegrin, Fariba Nemati, Emmanuel Donnadieu, Gérald Massonnet, Martine Pugnière, Didier Meseure, Didier Decaudin, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut Curie [Paris], UMR 5146 - Laboratoire Claude Goux (LCG-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Oncologie Expérimentale, PIERRE FABRE, GamaMabs Pharma SA [Toulouse] ( Centre Pierre Potier), Oncopole de Toulouse-Centre Pierre Potier [Toulouse], Immunociblage et radiobiologie en oncologie, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), and Salvy-Córdoba, Nathalie

Subjects
0301 basic medicine, medicine.drug_class, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Immunofluorescence, Monoclonal antibody, chemotherapy, human ovarian cancers, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Medicine, Antibody-dependent cell-mediated cytotoxicity, Chemotherapy, medicine.diagnostic_test, business.industry, tumor-associated macrophages, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 3. Good health, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, patient-derived xenografts (PDXs), 030104 developmental biology, Oncology, Apoptosis, Immunology, Cancer research, Immunohistochemistry, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, Ovarian cancer, Müllerian hormone type II receptor, Research Paper
Abstract

International audience; Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials.

Published
2017

6. Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

Author

Virginie Dangles-Marie, Eric Angevin, Sophie Vacher, Elisabetta Marangoni, Ludmilla de Plater, Fariba Nemati, Sergio Roman-Roman, Rana Hatem, Ivan Bièche, Ahmed Dahmani, Didier Decaudin, Sophie Richon, David Vallerand, Laboratoire d'Oncogénétique, CRLCC René Huguenin-Institut Curie [Paris], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Recherche Translationnelle, Institut Curie [Paris], Service d'Oncologie, Roche SAS, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Département d'Oncologie Médicale, Centre de Recherche, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Institut Curie [Paris], This work was supported by the Comité départemental des Hauts-de-Seine de la Ligue Nationale Contre le Cancer , the Conseil régional d'Ile-de-France , the Cancéropôle Ile-de-France and the Association pour la recherche en cancérologie de Saint-Cloud (ARCS), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-PRES Sorbonne Paris Cité, BMC, Ed., CRLCC René Huguenin-INSTITUT CURIE, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSTITUT CURIE, Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Institut Gustave Roussy ( IGR ), and Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-INSTITUT CURIE

Subjects
Vascular Endothelial Growth Factor A, CD31, Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, Species-specific PCR assays, Cell, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor vasculature, Biomarkers, Tumor, Genetics, medicine, Animals, Humans, Autocrine signalling, Patient-deriv ed xenografts, Endothelial markers, business.industry, VEGFA-VEGFR1/2 signalings, Gene Expression Profiling, Endothelial Cells, Cancer, Neoplasms, Experimental, Endoglin, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Bevacizumab, Gene Expression Regulation, Neoplastic, Patient-derived xenografts, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, medicine.anatomical_structure, Oncology, Cancer cell, cardiovascular system, Female, business, Signal Transduction, Research Article
Abstract

International audience; BACKGROUND: Tumor endothelial transdifferentiation and VEGFR1/2 expression by cancer cells have been reported in glioblastoma but remain poorly documented for many other cancer types. METHODS: To characterize vasculature of patient-derived tumor xenografts (PDXs), largely used in preclinical anti-angiogenic assays, we designed here species-specific real-time quantitative RT-PCR assays. Human and mouse PECAM1/CD31, ENG/CD105, FLT1/VEGFR1, KDR/VEGFR2 and VEGFA transcripts were analyzed in a large series of 150 PDXs established from 8 different tumor types (53 colorectal, 14 ovarian, 39 breast and 15 renal cell cancers, 6 small cell and 5 non small cell lung carcinomas, 13 cutaneous melanomas and 5 glioblastomas) and in two bevacizumab-treated non small cell lung carcinomas xenografts. RESULTS: As expected, mouse cell proportion in PDXs -evaluated by quantifying expression of the housekeeping gene TBP- correlated with all mouse endothelial markers and human VEGFA RNA levels. More interestingly, we observed human PECAM1/CD31 and ENG/CD105 expression in all tumor types, with higher rate in glioblastoma and renal cancer xenografts. Human VEGFR expression profile varied widely depending on tumor types with particularly high levels of human FLT1/VEGFR1 transcripts in colon cancers and non small cell lung carcinomas, and upper levels of human KDR/VEGFR2 transcripts in non small cell lung carcinomas. Bevacizumab treatment induced significant low expression of mouse Pecam1/Cd31, Eng/Cd105, Flt1/Vegfr1 and Kdr/Vefr2 while the human PECAM1/CD31 and VEGFA were upregulated. CONCLUSIONS: Taken together, our results strongly suggest existence of human tumor endothelial cells in all tumor types tested and of both stromal and tumoral autocrine VEGFA-VEGFR1/2 signalings. These findings should be considered when evaluating molecular mechanisms of preclinical response and resistance to tumor anti-angiogenic strategies.

Published
2014

7. Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters

Author

Marc Sitbon, Jawida Touhami, Vincent Petit, Didier Decaudin, Julie Laval, Naomi Taylor, Jean-Jacques Fontaine, David Vallerand, Aurélie Thuleau, Jean-Luc Servely, Fariba Nemati, Sophie Château-Joubert, Zofia Maciorowski, Gérald Massonnet, Jean-Luc Battini, Department of Ocean Engineering (DOE/URI), University of Rhode Island (URI), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
Cell Survival, Metabolite, Cell, Transplantation, Heterologous, Mice, Nude, Breast Neoplasms, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cell Line, Tumor, medicine, Biomarkers, Tumor, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, 0303 health sciences, Analysis of Variance, Cluster of differentiation, biology, Drug discovery, Cell Membrane, Membrane Transport Proteins, Reproducibility of Results, Transporter, Cell Biology, Flow Cytometry, Immunohistochemistry, 3. Good health, Cell biology, Metabolic pathway, medicine.anatomical_structure, Hyaluronan Receptors, Biochemistry, chemistry, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, GLUT1, Female, Neoplasm Transplantation
Abstract

Metabolic adaptations and changes in the expression of nutrient transporters are known to accompany tumorigenic processes. Nevertheless, in the context of solid tumors, studies of metabolism are hindered by a paucity of tools allowing the identification of cell surface transporters on individual cells. Here, we developed a method for the dissociation of human breast cancer tumor xenografts combined with quantification of cell surface markers, including metabolite transporters. The expression profiles of four relevant nutrient transporters for cancer cells' metabolism, Glut1, ASCT2, PiT1 and PiT2 (participating to glucose, glutamine and inorganic phosphate, respectively), as detected by new retroviral envelope glycoprotein-derived ligands, were distinctive of each tumor, unveiling underlying differences in metabolic pathways. Our tumor dissociation procedure and nutrient transporter profiling technology provides opportunities for future basic research, clinical diagnosis, prognosis and evaluation of therapeutic responses, as well as for drug discovery and development.Laboratory Investigation advance online publication, 4 March 2013; doi:10.1038/labinvest.2013.44.

Published
2013

8. Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

Author

Sergio Roman-Roman, Emmanuel Barillot, Bérengère Marty-Prouvost, Aurélie Dumont, Thierry Dubois, Marion Richardson, Leanne De Koning, Virginie Maire, Bruno Tesson, Stéphane Depil, Gordon C. Tucker, Francisco Cruzalegui, Anne Vincent-Salomon, Elisabetta Marangoni, Didier Decaudin, Alain Pierré, Guillem Rigaill, Fariba Nemati, Eléonore Gravier, Guillaume Lang, David Gentien, Translat Res Dept, CHU Pitié-Salpêtrière [APHP], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathématiques et Informatique Appliquées (MIA-Paris), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Dept Biostat, Institut de Recherches Servier, Dept Reverse Phase Prot Array Platform, Platform Mol Biol Facil, Dept Med Oncol, Oncol Res & Dev Unit, Ctr Rech, Equipe Biol Canc Sein, Dept Rech Translat, Institut Curie, Canceropole Ile de France, AgroParisTech-Institut National de la Recherche Agronomique (INRA), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, 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), Breast Canc Biol Grp, Lab Preclin Invest, Dept Tumor Biol, INSERM U830, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Mathématiques et Informatique Appliquées ( MIA-Paris ), and Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech

Subjects
Cancer Research, TP53 MUTATION, INHIBITOR BI 2536, Cyclophosphamide, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Breast Neoplasms, Cell Cycle Proteins, CELL-LINES, Biology, Protein Serine-Threonine Kinases, INITIATING CELLS, 03 medical and health sciences, Mice, 0302 clinical medicine, Breast cancer, MAMMALIAN-CELLS, Cell Line, Tumor, Proto-Oncogene Proteins, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, Doxorubicin, Clonogenic assay, Triple-negative breast cancer, 030304 developmental biology, GENE-EXPRESSION, 0303 health sciences, Chemotherapy, Tissue microarray, [ SDV ] Life Sciences [q-bio], Pteridines, Cancer, ADVANCED SOLTUMORS, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Up-Regulation, PHASE-I, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, SCREEN, PLK1, medicine.drug
Abstract

Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G2–M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. Cancer Res; 73(2); 813–23. ©2012 AACR.

Published
2013

9. Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

Author

Anderson Clark, Didier Decaudin, Franck Assayag, Sophie Chateau-Joubert, Edward Spooner, Jean-Jacques Fontaine, Xiaohong Liu, Ivan Bièche, Samantha Goodstal, Angela Romanelli, Jean-Luc Servely, Marie-France Poupon, Patricia de Cremoux, Elisabetta Marangoni, EMD Serono Inc., Hôpital Saint-Louis, École nationale vétérinaire d'Alfort (ENVA), Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7), Hôpital René HUGUENIN (Saint-Cloud), and Institut Curie [Paris]

Subjects
CA15-3, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], PROTEIN, Targeted therapy, Mice, 0302 clinical medicine, Aurora kinase, Aurora Kinases, PF-03814735, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Triple-negative breast cancer, GENE-EXPRESSION, 0303 health sciences, ACUTE MYELOGENOUS LEUKEMIA, Kinase, Immunohistochemistry, 3. Good health, APOPTOSIS, Oncology, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, CHECKPOINT, Mice, Nude, Breast Neoplasms, Cell Growth Processes, Protein Serine-Threonine Kinases, ENDOREDUPLICATION, 03 medical and health sciences, Breast cancer, Cell Line, Tumor, medicine, Animals, Humans, [INFO]Computer Science [cs], Protein Kinase Inhibitors, 030304 developmental biology, B KINASE, Chemotherapy, business.industry, ANEUPLOIDY, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Immunology, CELLS, Cancer research, business
Abstract

Triple-negative breast cancers (TNBC) have an aggressive phenotype with a relatively high rate of recurrence and poor overall survival. To date, there is no approved targeted therapy for TNBCs. Aurora kinases act as regulators of mammalian cell division. They are important for cell-cycle progression and are frequently overexpressed or mutated in human tumors, including breast cancer. In this study, we investigated the therapeutic potential of targeting Aurora kinases in preclinical models of human breast cancers using a pan-inhibitor of Aurora kinases, AS703569. In vitro, AS703569 was tested in 15 human breast cancer cell lines. TNBC cell lines were more sensitive to AS703569 than were other types of breast cancer cells. Inhibition of proliferation was associated with cell-cycle arrest, aneuploidy, and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in seven of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated with a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin–cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that Aurora kinase inhibitors could be used both in monotherapy and in combination settings. In conclusion, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment. Mol Cancer Ther; 11(12); 2693–703. ©2012 AACR.

Published
2012

10. Hepatitis C virus infection and MALT-type ocular adnexal lymphoma

Author

Marie Christine Escande, Pierre Validire, Olivier Hermine, Anne Vincent-Salomon, Corine Plancher, Nicole Brousse, Marc Lecuit, P. de Cremoux, Philippe Arnaud, Didier Decaudin, Christine Levy, Institut Curie [Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
business.industry, Hepatitis C virus, [SDV]Life Sciences [q-bio], Hematology, Seroepidemiologic Studies, medicine.disease, medicine.disease_cause, Virology, Lymphoma, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Ocular Adnexal Lymphoma, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, Medicine, business, B cell, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

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