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31 results on '"MESH: Quinazolines"'

1. Identification of novel quinazoline derivatives as potent antiplasmodial agents

Author

Johan Schultz, Dany Pechalrieu, Sergio Valente, Anne Bouchut, Tina S. Skinner-Adams, Giancarlo Fabrizi, Paola B. Arimondo, Urban Hoglund, Katherine T. Andrews, Roberta Mazzone, Sophia Lafitte, Antonello Mai, Alessia Lucidi, Christine Pierrot, Ming Jang Chua, Jamal Khalife, Dante Rotili, Institut Pasteur de Lille, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] [UNIROMA], Pharmacochimie de la Régulation Epigénétique du Cancer [ETaC], Réseau International des Instituts Pasteur (RIIP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Kancera AB [Sweden], Adlego Biomedical AB [Sweden], Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), GRIFFITH UNIVERSITY AUS, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), This work was supported by the Australian National Health and Medical Research Council (APP1074016 to K.T.A.), Italian PRIN 2016 (prot. 20152TE5PK to A.M.), AIRC 2016 (n. 19162 to A.M.), NIH (n. R01GM114306 to A.M.), Progetto Ateneo Sapienza 2017 (to D.R.), the A-ParaDDisE program funded under the European Union's Seventh Framework Programme (grant agreement no. 602080 to A.B., C.P., S.L., A.M., D.R., S.V., J.S., U.H., K.T.A. and J.K.) and Griffith University (GUIPRS and GUPRS scholarships to M.J.C.). We thank Mary Clarke (Griffith University) for technical assistance. We also thank the BioImaging Center Lille Facility for access to the BD FACSCanto II cytometer., European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Griffith University [Brisbane], Centre d’Infection et d’Immunité de Lille (CIIL) - INSERM U1019 - UMR 9017 (CIIL), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Università degli Studi di Roma 'La Sapienza' [Rome], and PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium berghei, Molecular Conformation, Pharmacology, MESH: Parasitic Sensitivity Tests, 01 natural sciences, Antimalarial agents, MESH: Dose-Response Relationship, Drug, Mice, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, PK studies, Histone deacetylase inhibitors, Drug Discovery, P. berghei mouse model, MESH: Animals, Antimalarial Agent, DNA methyltransferase inhibitors, Artemisinin, MESH: Plasmodium falciparum, media_common, 0303 health sciences, Mice, Inbred BALB C, biology, Chemistry, General Medicine, 3. Good health, MESH: Quinazolines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.drug, Drug, antimalarial agents, histone deacetylase inhibitors, media_common.quotation_subject, Plasmodium falciparum, MESH: Mice, Inbred BALB C, Context (language use), 03 medical and health sciences, Antimalarials, Structure-Activity Relationship, In vivo, parasitic diseases, medicine, MESH: Plasmodium berghei, [CHIM]Chemical Sciences, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Molecular Conformation, MESH: Humans, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, Fibroblasts, biology.organism_classification, medicine.disease, MESH: Antimalarials, 0104 chemical sciences, MESH: Fibroblasts, Quinazolines, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Malaria
Abstract

International audience; Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed to target different epigenetic enzymes were screened for activity against Plasmodium falciparum parasites. Based on in vitro activity against drug susceptible and drug-resistant P. falciparum lines, selectivity index criterion and favorable pharmacokinetic properties, four compounds, one HDAC inhibitor (1) and three DNMT inhibitors (37, 43 and 45), were selected for preclinical studies in a mouse model of malaria. In vivo data showed that 37, 43 and 45 exhibited oral efficacy in the mouse model of Plasmodium berghei infection. These compounds represent promising starting points for the development of novel antimalarial drugs.

Published
2019
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2. Long-Term Control of Hypercortisolism by Vandetanib in a Case of Medullary Thyroid Carcinoma with a Somatic RET Mutation

Author

Marie Bienvenu-Perrard, Anne-Cécile Paepegaey, Najiba Lahlou, Lionel Groussin, Estelle Louiset, Léopoldine Bricaire, Béatrix Cochand-Priollet, Marco Alifano, Nelly Burnichon, Pierre-Olivier Sarfati, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, Hydrocortisone, MESH: Carcinoma, Neuroendocrine, Somatic cell, Endocrinology, Diabetes and Metabolism, Cushing's syndrome, Vandetanib, MESH: Cushing Syndrome, 0302 clinical medicine, Endocrinology, Piperidines, medullary thyroid carcinoma, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Protein Kinase Inhibitors, Cushing Syndrome, MESH: Middle Aged, Cytoreduction Surgical Procedures, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Debulking, MESH: Hydrocortisone, 3. Good health, MESH: Quinazolines, MESH: Piperidines, MESH: Thyroid Neoplasms, 030220 oncology & carcinogenesis, Thyroidectomy, Neck Dissection, Tyrosine kinase, Long term control, medicine.drug, Calcitonin, medicine.medical_specialty, vandetanib, Medullary cavity, 030209 endocrinology & metabolism, MESH: Proto-Oncogene Proteins c-ret, MESH: Thyroidectomy, Thyroid carcinoma, 03 medical and health sciences, Internal medicine, MESH: Neck Dissection, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, MESH: Cytoreduction Surgical Procedures, Thyroid Neoplasms, Protein Kinase Inhibitors, MESH: Humans, hypercortisolism, MESH: Calcitonin, business.industry, Proto-Oncogene Proteins c-ret, MESH: Male, Carcinoma, Neuroendocrine, Quinazolines, business, RET
Abstract

Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies.The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753TC) somatic mutation was identified in a lymph node metastasis.Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.

Published
2017
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3. Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3

Author

Nicolas Richard, Pierre Hainaut, Bruno Coudert, Xavier Sastre-Garau, Jean-Luc Prétet, Yves-Marie ROBIN, Christos Chouaid, Stefan Michiels, Pierre-Emmanuel Falcoz, Pascal Reynier, Marie Wislez, CHRISTIANE MOUGIN, Patrice VIENS, Helene Blons, Isabelle Borget, Jean-Pierre PIGNON, Denis MORO-SIBILOT, Ivan Bieche, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de compétences pour les maladies pulmonaires rares, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Strasbourg, Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Université de Lille-UNICANCER

Subjects
Male, Oncology, Lung Neoplasms, Cost effectiveness, Cost-Benefit Analysis, Medical Oncology, MESH: ErbB Receptors, 0302 clinical medicine, Quality of life, Carcinoma, Non-Small-Cell Lung, MESH: Erlotinib Hydrochloride, MESH: Protein Kinase Inhibitors, 030212 general & internal medicine, Epidermal growth factor receptor, 10. No inequality, Erlotinib Hydrochloride, MESH: Medical Oncology, MESH: Aged, MESH: Middle Aged, biology, Middle Aged, Markov Chains, 3. Good health, ErbB Receptors, MESH: Quinazolines, Docetaxel, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Erlotinib, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, 03 medical and health sciences, MESH: Markov Chains, Internal medicine, Carcinoma, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Aged, MESH: Humans, business.industry, MESH: Quality of Life, medicine.disease, MESH: Male, MESH: Sensitivity and Specificity, MESH: Lung Neoplasms, respiratory tract diseases, Surgery, Mutation, Quality of Life, Quinazolines, biology.protein, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung, MESH: Cost-Benefit Analysis
Abstract

International audience; Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

Published
2011
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4. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Author

Michel Doffoel, Marine Turek, Isabel Fofana, Olivier Poch, Muhammad N. Zahid, Patrick Pessaux, Thomas F. Baumert, Fei Xiao, Laetitia Zona, Christopher Davis, Sebastian Gorke, S. Michael Rothenberg, François-Loïc Cosset, Mirjam B. Zeisel, Laurent Brino, Dimitri Lavillette, Cathy Royer, Thomas Pietschmann, Wolfgang Raffelsberger, Benoit Fischer, Jane A. McKeating, Judith Fresquet, Christopher J. Mee, Arvind H. Patel, Joachim Lupberger, Christine Thumann, Baumert, Thomas F., Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hepatitis C Research Group, Division of Immunity and Infection-University of Birmingham [Birmingham], Department of Medicine II, University of Freiburg [Freiburg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital Cancer Center, Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), MRC Virology Unit, University of Glasgow, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Strasbourg-Nouvel Hôpital Civil, ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009, ANR-05-CEXC-008, ANRS 2008/354, Région Alsace, INCa, NIH, MRC and the Wellcome Trust., École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
MESH: Virus Internalization, Hepacivirus, MESH: Base Sequence, Ligands, medicine.disease_cause, Receptor tyrosine kinase, Mice, Cell-cell transmission, 0302 clinical medicine, Claudin-1, MESH: RNA, Small Interfering, MESH: Ligands, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Hepacivirus, Epidermal growth factor receptor, RNA, Small Interfering, MESH: Antigens, CD, MESH: Receptor, EphA2, 0303 health sciences, Phosphotyrosine kinase, biology, Receptor, EphA2, virus diseases, General Medicine, EPH receptor A2, Hepatitis C, 3. Good health, ErbB Receptors, MESH: Quinazolines, Liver, Host-Pathogen Interactions, RNA Interference, 030211 gastroenterology & hepatology, MESH: Membrane Proteins, Tyrosine kinase, MESH: Antiviral Agents, Hepatitis C virus, MESH: RNA Interference, MESH: Receptor, Epidermal Growth Factor, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Tetraspanin 28, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Antigens, CD81, Antigens, CD, Viral entry, medicine, Animals, Humans, Antiviral, Kinase activity, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Base Sequence, MESH: Host-Pathogen Interactions, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virus Internalization, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cell Line, HCV escape variants, Quinazolines, biology.protein
Abstract

International audience; Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.

Published
2011
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5. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

Author

Sophie Rigaudeau, Giovanni Martinelli, Pieter Sonneveld, Alison Goudie, Ellin Berman, Sergio Amadori, Hagop M. Kantarjian, Bob Löwenberg, Norbert Ifrah, Philippe Rousselot, Stefan Faderl, Paul K. Stockman, Elias Jabbour, Petra Muus, Gert J. Ossenkoppele, Mojca Jongen-Lavrencic, Jean-Yves Cahn, Hematology, CCA - Innovative therapy, Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Haematology, European Institute of Oncology [Milan] (ESMO), Department of Biopathology, and Università degli Studi di Roma Tor Vergata [Roma]

Subjects
Myeloid, Male, Clinical Trials and Observations, Pharmacology, Biochemistry, Gastroenterology, Severity of Illness Index, MESH: Dose-Response Relationship, Drug, MESH: Aged, 80 and over, 0302 clinical medicine, Aurora Kinases, Recurrence, hemic and lymphatic diseases, 80 and over, MESH: Protein Kinase Inhibitors, Aurora Kinase B, Stomatitis, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, Leukemia, Myeloid leukemia, Hematology, Middle Aged, Protein-Serine-Threonine Kinases, Hematologic Response, Organophosphates, 3. Good health, MESH: Quinazolines, Leukemia, Myeloid, Acute, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Toxicity, Female, Drug, MESH: Leukemia, Myeloid, Acute, medicine.medical_specialty, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Acute, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, Dose-Response Relationship, 03 medical and health sciences, Pharmacokinetics, Translational research [ONCOL 3], MESH: Severity of Illness Index, Internal medicine, medicine, Humans, Protein Kinase Inhibitors, 030304 developmental biology, Aged, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Quinazolines, Cell Biology, medicine.disease, MESH: Male, MESH: Recurrence, business, MESH: Female, MESH: Organophosphates, Settore MED/15 - Malattie del Sangue, Febrile neutropenia
Abstract

The primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.

Published
2011
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6. Economics of Treatments for Non-Small Cell Lung Cancer

Author

Christos Chouaid, Alain Vergnenegre, Kukovi Atsou, Gilles Hejblum, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, C Chouaid, K Atsou, G Hejblum, SCHILLER A, Pôle de Pharmacie - Santé Publique - Information médicale [Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Oncology, MESH: Combined Modality Therapy, Lung Neoplasms, Cost effectiveness, Cost-Benefit Analysis, MESH: Taxoids, Docetaxel, 0302 clinical medicine, Glutamates, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Medicine, 030212 general & internal medicine, health care economics and organizations, Health Policy, Combined Modality Therapy, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Quinazolines, Pemetrexed, 030220 oncology & carcinogenesis, Taxoids, Erlotinib, medicine.drug, medicine.medical_specialty, Guanine, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Glutamates, Internal medicine, Humans, Lung cancer, MESH: Guanine, Pharmacology, MESH: Humans, Performance status, business.industry, Public Health, Environmental and Occupational Health, Cancer, medicine.disease, MESH: Lung Neoplasms, respiratory tract diseases, Surgery, Localized disease, Quinazolines, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Carcinoma, Non-Small-Cell Lung, MESH: Cost-Benefit Analysis
Abstract

International audience; The purpose of this article is to review the economics of treatments for non-small cell lung cancer (NSCLC). We systematically analysed the cost effectiveness of treatments for the different stages of NSCLC, with particular emphasis on more recently approved agents. Numerous economic analyses in NSCLC have been conducted, with a variety of methods and in a number of countries. In patients with localized disease, adjuvant chemotherapy appears to have greater cost effectiveness than observation; however, there are few published data. In locally advanced disease, combined modalities (chemotherapy, surgery and/or radiotherapy) are probably cost effective, but high-quality economic analyses are lacking. In advanced NSCLC, third-generation chemotherapies used in the first-line setting can be administered with acceptable incremental cost effectiveness. In the second-line setting, new agents (docetaxel, pemetrexed and erlotinib) have acceptable cost effectiveness. The lack of cost-utility analyses for elderly patients and patients with a poor prognosis rules out firm conclusions. This review suggests that most therapies for NSCLC are cost effective when the patient has a good performance status, with an incremental cost-effectiveness ratio under USD 50,000 per life-year gained in the majority of cases.

Published
2009
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7. Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans

Author

Santiago Ferrer, María Santos Martínez, Laura M. Sanz, Sergio Wittlin, Michael J. Delves, Joachim Caron, Nicholas A. Malmquist, Didier Menard, Matthew J. Fuchter, François Nosten, Robert E. Sinden, Artur Scherf, Patty Chen, Francisco-Javier Gamo, María Belén Jiménez-Díaz, Sandeep Sundriyal, Rossarin Suwanarusk, Laurent Rénia, Sandra Duffy, Iñigo Angulo-Barturen, Andrea Ruecker, Benoit Witkowski, Vicky M. Avery, Biologie des Interactions Hôte-Parasite, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry [Imperial College London], Imperial College London, Laboratoire d'épidémiologie moléculaire, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Diseases of the Developing World [Tres Cantos, Madrid] (DDW), Tres Cantos Open Lab Foundation [London, UK] (TCOLF)-GlaxoSmithKline [Headquarters, London, UK] (GSK), Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), Eskitis Institute for Drug Discovery, Griffith University [Brisbane], S.S. acknowledges the European Commission for a Marie Curie International Incoming Fellowship (agreement no. 299857). L.R. was supported by funding from the Singapore Immunology Network (SIgN) and the Horizontal Programme on Infectious Diseases under the Agency for Science, Technology and Research (A*STAR, Singapore). The Shoklo Malaria Research Unit is part of the Mahidol Oxford University Research Unit, supported by the Wellcome Trust of Great Britain. V.M.A. acknowledges support from the Australian Research Council (LP120200557). A.S. acknowledges support from the European Research Council., We thank Xavier Ding and Brice Campo of the Medicines for Malaria Venture for helpful discussions and aid in coordinating some of the collaborative efforts. We thank Jolanda Kamber for assistance in performing the P. berghei in vivo assay and Christoph Siethoff (Swiss BioQuant) for the determination of compound levels in P. berghei-infected mice. We are also grateful to the Therapeutic Efficacy, Pharmacology, and Laboratory Animal Science groups at GSK Tres Cantos Medicines Development Campus for assistance. We thank L. D. Shultz and The Jackson Laboratory for providing access to nonobese diabetic SCID IL-2Rγcnull mice through their collaboration with GSK Tres Cantos Medicines Development Campus. We are indebted to Susan A. Charman of Monash University for critically reviewing the manuscript., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Oxford-University of Oxford, and University of Oxford-Mahidol University [Bangkok]

Subjects
MESH: Histone Methyltransferases, Plasmodium berghei, Plasmodium vivax, Mice, SCID, Pharmacology, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pharmacology (medical), MESH: Animals, Artemisinin, Malaria, Falciparum, MESH: Mice, SCID, MESH: Plasmodium falciparum, biology, MESH: Malaria, Falciparum, Azepines, Hep G2 Cells, 3. Good health, MESH: Quinazolines, Infectious Diseases, Histone Methyltransferases, Female, medicine.drug, Plasmodium falciparum, MESH: Malaria, MESH: Hep G2 Cells, Antimalarials, In vivo, parasitic diseases, medicine, Gametocyte, Animals, Humans, MESH: Plasmodium berghei, Experimental Therapeutics, MESH: Mice, MESH: Humans, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, biology.organism_classification, Virology, MESH: Antimalarials, Malaria, Multiple drug resistance, Quinazolines, MESH: Azepines, MESH: Female, Ex vivo
Abstract

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC 50 s) of Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.

Published
2015
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8. Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

Author

Manfred Jung, Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Veronique Masson, Valerie Poughon, Frederic Ausseil, Yanqi Chang, Donatella Labella, Sandro Cosconati, Salvatore Di Maro, Michael Schnekenburger, Cindy Grandjenette, Celine Bouvy, Marc Diederich, Xiaodong Cheng, Paola B. Arimondo, Antonello Mai, NOVELLINO, ETTORE, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-PIERRE FABRE, Emory University School of Medicine, Emory University [Atlanta, GA], Seconda Università degli studi di Napoli, Università degli studi di Napoli Federico II, Laboratoire de Biologie Moléculaire et Cellulaire du Cancer [Luxembourg] (LBMCC), Hôpital Kirchberg [Luxembourg], Seoul National University [Seoul] (SNU), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), This work was supported by PRIN 2009PX2T2E, FIRB RBFR10ZJQT, Progetto Ateneo Sapienza 2012, Progetto IIT-Sapienza, FP7 Projects BLUEPRINT/282510 and COST/TD0905, the U.S. National Institutes of Health (5R01GM049245-20 and 1DP3DK094346-01), the FNRS Télévie Luxembourg grant 7.4612.12.F, the «Recherche Cancer et Sang foundation, and the «Recherches Scientifiques Luxembourg and «Een Häerz fir Kriibskrank Kanner associations. X. Cheng is a Georgia Research Alliance Eminent Scholar. P.B. Arimondo is supported by ATIP CNRS and Région Midi-Pyrenées (Equipe d’Excellence and FEDER). M. Schnekenburger is supported by a 'Waxweiler grant for cancer prevention research' from the Action Lions 'Vaincre le Cancer'. C. Gros is supported by Fondation de la Recherche Médicale. C. Grandjenette is a recipient of a postdoctoral grant from FNRS Télévie Luxembourg. M. Diederich is supported by the NRF by the MEST of Korea for Tumor Microenvironment GCRC 2012-0001184 grant., European Project: 282510,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,BLUEPRINT(2011), Rotili, D, Tarantino, D, Marrocco, B, Gros, C, Masson, V, Poughon, V, Ausseil, F, Chang, Y, Labella, D, Cosconati, Sandro, DI MARO, Salvatore, Novellino, E, Schnekenburger, M, Grandjenette, C, Bouvy, C, Diederich, M, Cheng, X, Arimondo, Pb, Mai, A., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Seconda Università degli Studi di Napoli = Second University of Naples, University of Naples Federico II = Università degli studi di Napoli Federico II, Manfred, Jung, Dante, Rotili, Domenico, Tarantino, Biagina, Marrocco, Christina, Gro, Veronique, Masson, Valerie, Poughon, Frederic, Ausseil, Yanqi, Chang, Donatella, Labella, Sandro, Cosconati, Salvatore Di, Maro, Novellino, Ettore, Michael, Schnekenburger, Cindy, Grandjenette, Celine, Bouvy, Marc, Diederich, Xiaodong, Cheng, Paola B., Arimondo, and Antonello, Mai

Subjects
Methyltransferase, Cancer Treatment, lcsh:Medicine, MESH: Catalytic Domain, Biochemistry, DNA Methyltransferase 3A, MESH: Structure-Activity Relationship, Catalytic Domain, Histocompatibility Antigens, Molecular Cell Biology, Medicine and Health Sciences, DNA (Cytosine-5-)-Methyltransferases, Enzyme Inhibitors, lcsh:Science, Multidisciplinary, biology, Cell Death, Chemical Synthesis, Histone Modification, Heterocycle Structures, Methylation, Azepines, 3. Good health, Molecular Docking Simulation, Chemistry, MESH: Quinazolines, Histone, Oncology, MESH: Cell Survival, Cell Processes, MESH: Enzyme Inhibitors, Histone methyltransferase, DNA methylation, Physical Sciences, Epigenetics, DNA modification, Research Article, MESH: DNA (Cytosine-5-)-Methyltransferases, MESH: Cell Line, Tumor, Cell Survival, Research and Analysis Methods, DNA methyltransferase, Cell Growth, Epigenetic Therapy, Histone H3, Structure-Activity Relationship, Cell Line, Tumor, MESH: Cell Proliferation, Genetics, MESH: Molecular Docking Simulation, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Proliferation, MESH: Humans, Biology and life sciences, lcsh:R, Organic Chemistry, MESH: Histocompatibility Antigens, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, DNA, Cell Biology, Molecular biology, biology.protein, DNMT1, Quinazolines, lcsh:Q, Medicinal Chemistry, MESH: Azepines
Abstract

International audience; Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.

Published
2014
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9. STLC-resistant cell lines as tools to classify chemically divergent Eg5 targeting agents according to their mode of action and target specificity

Author

Isabel Garcia-Saez, Salvatore DeBonis, Frank Kozielski, Dimitrios A. Skoufias, Rose-Laure Indorato, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Thomas, Frank

Subjects
MESH: Cell Line, Tumor, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Allosteric regulation, Kinesins, Antineoplastic Agents, MESH: Thiadiazoles, Biology, Biochemistry, Adenosine Triphosphate, Cell Line, Tumor, MESH: Cell Proliferation, Thiadiazoles, MESH: Adenosine Triphosphate, medicine, MESH: Adenosine Triphosphatases, Humans, Point Mutation, Cysteine, Mode of action, MESH: Allosteric Site, Mitosis, Cell Proliferation, MESH: Point Mutation, Pharmacology, Adenosine Triphosphatases, Binding Sites, MESH: Humans, MESH: M Phase Cell Cycle Checkpoints, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Thiones, Transfection, MESH: Cysteine, Small molecule, MESH: Drug Resistance, Neoplasm, MESH: Quinazolines, Mechanism of action, MESH: Binding Sites, Drug Resistance, Neoplasm, Quinazolines, Kinesin, M Phase Cell Cycle Checkpoints, MESH: Antineoplastic Agents, MESH: Thiones, medicine.symptom, Centrosome separation, MESH: Kinesin, Allosteric Site
Abstract

International audience; Determining the mechanism of action of drugs and their target specificity in cells remains a major challenge. Here we describe the use of cell lines expressing two point mutations in the allosteric inhibitor binding pocket of the mitotic kinesin Eg5 (D130A, in the loop L5 region and L214A in helix α3), which following transfection, were selected for their ability to proliferate normally in the presence of STLC, a well known Eg5 inhibitor. The cell lines were used to discriminate the mechanism of action of other chemically distinct small molecule inhibitors of Eg5 that differ in their mode of action. The STLC resistant cells were capable of continuous proliferation in the presence of ATP uncompetitive inhibitors, such as K858 and dimethylenastron, but were still sensitive to ATP competitive inhibitors that are thought to bind to a distinct site on Eg5 than the allosteric binding pocket. The STLC resistant cell lines can therefore be used as a filter to distinguish Eg5 loop L5 binding drugs from drugs binding to other pockets without prior structural information. Additionally, the cells can be used to analyze whether inhibitors of Eg5 are specific to this potential drug target or whether they have additional targets in dividing cells.

Published
2013

10. Phenylpyrazolo[1,5‑a]quinazolin-5(4H)‑one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors

Author

Anna Maria Marini, Christophe Marchand, Keli Agama, Luciana Marinelli, Concettina La Motta, Francesco Saverio Di Leva, Sabrina Taliani, Ettore Novellino, Silvia Salerno, Yves Pommier, Roberto Di Santo, Elisabetta Barresi, Federico Da Settimo, Francesca Simorini, Sandro Cosconati, Isabella Pugliesi, Taliani, S, Pugliesi, I, Barresi, E, Salerno, S, Marchand, C, Agama, K, Simorini, F, La Motta, C, Marini, Am, Di Leva, F, Marinelli, L, Cosconati, Sandro, Novellino, E, Pommier, Y, Di Santo, R, Da Settimo, F., Department of Pharmacy, University of Pisa - Università di Pisa, Laboratory of Molecular Pharmacology, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Pharmaceutical Chemistry and Toxicology, Università degli studi di Napoli Federico II, Department of Pharmacy Naples, Université de Naples, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], S., Taliani, I., Pugliesi, E., Barresi, S., Salerno, C., Marchand, K., Agama, F., Simorini, C., La Motta, A. M., Marini, Di Leva, Francesco Saverio, Marinelli, Luciana, S., Cosconati, Novellino, Ettore, Y., Pommier, R., Di Santo, and F., Da Settimo

Subjects
Protein Conformation, Stereochemistry, Topoisomerase-I Inhibitor, 010402 general chemistry, Cleavage (embryo), 01 natural sciences, Molecular Docking Simulation, Article, antitumor agents, chemistry.chemical_compound, MESH: Protein Conformation, MESH: Drug Discovery, Drug Discovery, inhibitors, Side chain, Quinazoline, MESH: Molecular Docking Simulation, Humans, Pyrroles, MESH: Heterocyclic Compounds, 3-Ring, topoisomerase, MESH: Humans, biology, 010405 organic chemistry, Drug discovery, Chemistry, Topoisomerase, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 0104 chemical sciences, MESH: Quinazolines, MESH: Topoisomerase I Inhibitors, DNA Topoisomerases, Type I, Docking (molecular), Quinazolines, biology.protein, MESH: Pyrroles, Molecular Medicine, Topoisomerase I Inhibitors, Heterocyclic Compounds, 3-Ring, MESH: DNA Topoisomerases, Type I
Abstract

In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol. © 2013 American Chemical Society.

Published
2013
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11. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.: p130Cas Over-Expression in Pulmonary Hypertension

Author

Tu, Ly, De Man, Frances, Girerd, Barbara, Huertas, Alice, Chaumais, Marie-Camille, Lecerf, Florence, François, Charlène, Perros, Frédéric, Dorfmüller, Peter, Fadel, Elie, Montani, David, Eddahibi, Saadia, Humbert, Marc, Guignabert, Christophe, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue, and Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Signal Transduction, MESH: Epidermal Growth Factor, MESH: Rats, MESH: Pulmonary Artery, MESH: Piperazines, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Signal transduction, Pulmonary arterial hypertension, MESH: Monocrotaline, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Endothelial Cells, MESH: Mice, Pulmonary vascular remodeling, MESH: Quinolones, MESH: Humans, MESH: Fibroblast Growth Factor 2, MESH: Hypertension, Pulmonary, MESH: Platelet-Derived Growth Factor, MESH: Myocytes, Smooth Muscle, MESH: Case-Control Studies, MESH: Crk-Associated Substrate Protein, MESH: Quinazolines, MESH: Pyrimidines, embryonic structures, BCAR1, MESH: Disease Models, Animal, Growth factors, MESH: Benzimidazoles
Abstract

International audience; RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival. OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension. CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

Published
2012
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12. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.: p130Cas Over-Expression in Pulmonary Hypertension

Author

Tu, Ly, de Man, Frances, Girerd, Barbara, Huertas, Alice, Chaumais, Marie-Camille, Lecerf, Florence, François, Charlène, Perros, Frédéric, Dorfmüller, Peter, Fadel, Elie, Montani, David, Eddahibi, Saadia, Humbert, Marc, Guignabert, Christophe, Guignabert, Christophe, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, and Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Signal Transduction, MESH: Epidermal Growth Factor, MESH: Rats, MESH: Pulmonary Artery, MESH: Piperazines, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Signal transduction, Pulmonary arterial hypertension, MESH: Monocrotaline, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Endothelial Cells, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Pulmonary vascular remodeling, MESH: Quinolones, MESH: Humans, MESH: Fibroblast Growth Factor 2, MESH: Hypertension, Pulmonary, MESH: Platelet-Derived Growth Factor, MESH: Myocytes, Smooth Muscle, MESH: Case-Control Studies, MESH: Crk-Associated Substrate Protein, MESH: Quinazolines, MESH: Pyrimidines, embryonic structures, BCAR1, MESH: Disease Models, Animal, Growth factors, MESH: Benzimidazoles
Abstract

International audience; RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival. OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension. CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

Published
2012
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13. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma

Author

Elisabeth Brambilla, Sandrine Dufort, Nathalie Rabbe, Martine Antoine, Denis Moro-Sibilot, Florence de Fraipont, C. Tenaud, Amandine Hurbin, Marie Wislez, Benoit Busser, Jacques Cadranel, Jean-Luc Coll, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie des Cancers et Biothérapies, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Biochimie des Cancers et Biothérapies, Pôle Médecine Aigüe Communautaire Pneumologie, CHU Grenoble, INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon-Hôpital Michallon-Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique-Intergroupe Francophone de Cancérologie thoracique, This work was supported by grants from 'La Ligue contre le Cancer, comité de l'Isère', 'projet libre INCa', 'Programme National d'Excellence Spécialisée 2005-2007 and Pharmacogenoscan PHRC 2003., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Oncology, MESH: Neoplasm Proteins, MESH: Adenocarcinoma, Mucinous, medicine.medical_treatment, medicine.disease_cause, Insulin-like growth factor, 0302 clinical medicine, MESH: Receptor, IGF Type 1, MESH: Aged, 80 and over, Epidermal growth factor, IGF1R, Neoplasm, MESH: Treatment Outcome, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Drug Resistance, Neoplasm, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, Adenocarcinoma, KRAS, amphiregulin, medicine.drug, medicine.medical_specialty, MESH: Mutation, mucinous, MESH: Glycoproteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, Pathology and Forensic Medicine, 03 medical and health sciences, Gefitinib, Amphiregulin, Internal medicine, EGFR-TKI, medicine, MESH: Tumor Cells, Cultured, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Insulin-like growth factor 1 receptor, MESH: Humans, business.industry, MESH: MAP Kinase Signaling System, MESH: Adenocarcinoma, MESH: Adult, medicine.disease, lung adenocarcinoma, MESH: Male, respiratory tract diseases, MESH: Lung Neoplasms, MESH: Tumor Markers, Biological, MESH: Antineoplastic Agents, business, MESH: Female, MESH: DNA-Binding Proteins
Abstract

International audience; The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non-mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component.

Published
2011
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14. Kinase inhibitors in the treatment of chronic hepatitis C virus

Author

Edouard Bardou-Jacquet, Dominique Guyader, R. Lorho, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Microenvironnement et remodelage, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service des maladies du foie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie [CHU Rennes], Centre Hospitalier Universitaire [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service des maladies du foie [CHU Rennes], and Centre Hospitalier Universitaire [Rennes]-Centre Hospitalier Universitaire [Rennes]

Subjects
MAPK/ERK pathway, Sorafenib, MESH: Antiviral Agents, MESH: Fatal Outcome, MESH: Liver Transplantation, 03 medical and health sciences, 0302 clinical medicine, medicine, MESH: Protein Kinase Inhibitors, Epidermal growth factor receptor, Protein kinase A, NS5A, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, Cyclin-dependent kinase 4, Cyclin-dependent kinase 2, Gastroenterology, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Follow-Up Studies, MESH: Male, 3. Good health, MESH: Hepatitis C, Chronic, MESH: Quinazolines, Cancer research, biology.protein, 030211 gastroenterology & hepatology, Erlotinib, medicine.drug
Abstract

We read with great interest the publication in Gut by Himmelsbach et al 1 in which they assessed whether the modulation of c-Raf by sorafenib affects hepatitis C virus (HCV) replication using the in vitro replicon system. The authors showed that sorafenib blocks HCV replication in vitro, by decreasing c-Raf phosphorylation and by affecting the post-translational processing of NS5A, which is required for the replication of the virus. We would like to report here a clinical observation that could suggest the clinical potential interest of kinase pathway inhibitors as a therapeutic option in chronic hepatitis C. Erlotinib is a highly selective kinase inhibitor targeting epidermal growth factor receptor (EGFR), the signalling pathway of which includes the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular-related-signal kinase (ERK) pathway. Erlotinib has been approved in non-small cell lung …

Published
2011
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15. Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies

Author

Gaborit, Nadège, Larbouret, Christel, Vallaghe, Julie, Peyrusson, Frédéric, Bascoul-Mollevi, Caroline, Crapez, Evelyne, Azria, David, Chardes, Thierry, Poul, Marie-Alix, Mathis, Gérard, Bazin, Hervé, Pèlegrin, André, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Cisbio, Research Department, and CIS BIOINTERNATIONAL

Subjects
MESH: Cell Line, Tumor, MESH: Humans, MESH: Phosphorylation, MESH: Fluorescence Resonance Energy Transfer, MESH: Protein Multimerization, MESH: Drug Screening Assays, Antitumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Receptors, Fibroblast Growth Factor, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Quinazolines, MESH: Antibodies, Neoplasm, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Receptor, erbB-2, MESH: Cell Proliferation, MESH: Protein Kinase Inhibitors, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, skin and connective tissue diseases, neoplasms, MESH: Mice, MESH: NIH 3T3 Cells
Abstract

International audience; In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation.

Published
2011
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16. Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies.: TR-FRET to quantify HER dimers and evaluate mAb efficiency

Author

Gaborit, Nadège, Larbouret, Christel, Vallaghe, Julie, Peyrusson, Frédéric, Bascoul-Mollevi, Caroline, Crapez, Evelyne, Azria, David, Chardes, Thierry, Poul, Marie-Alix, Mathis, Gérard, Bazin, Hervé, Pèlegrin, André, Le Ster, Yves, 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Cisbio, Research Department, and CIS BIOINTERNATIONAL

Subjects
MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Fluorescence Resonance Energy Transfer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Receptors, Fibroblast Growth Factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Cell Proliferation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, skin and connective tissue diseases, neoplasms, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: Humans, MESH: Phosphorylation, MESH: Protein Multimerization, MESH: Drug Screening Assays, Antitumor, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Quinazolines, MESH: Antibodies, Neoplasm, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Receptor, erbB-2, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: NIH 3T3 Cells
Abstract

International audience; In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation.

Published
2011
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17. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma.: IGF1R inhibition in mucinous lung adenocarcinoma

Author

Hurbin, Amandine, Wislez, Marie, Busser, Benoît, Antoine, Martine, Tenaud, Corine, Rabbe, Nathalie, Dufort, Sandrine, de Fraipont, Florence, Moro-Sibilot, Denis, Cadranel, Jacques, Coll, Jean-Luc, Brambilla, Elisabeth, Hurbin, Amandine, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie des Cancers et Biothérapies, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Service d'Anatomie et cytologie pathologiques [CHU Tenon], Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Biochimie des Cancers et Biothérapies, Pôle Médecine Aigüe Communautaire Pneumologie, CHU Grenoble, INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon-Hôpital Michallon-Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique-Intergroupe Francophone de Cancérologie thoracique, and This work was supported by grants from 'La Ligue contre le Cancer, comité de l'Isère', 'projet libre INCa', 'Programme National d'Excellence Spécialisée 2005-2007 and Pharmacogenoscan PHRC 2003.

Subjects
MESH: Neoplasm Proteins, MESH: Mutation, mucinous, MESH: Adenocarcinoma, Mucinous, MESH: Glycoproteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, MESH: Receptor, IGF Type 1, MESH: Aged, 80 and over, [SDV.CAN] Life Sciences [q-bio]/Cancer, IGF1R, EGFR-TKI, MESH: Tumor Cells, Cultured, MESH: Intercellular Signaling Peptides and Proteins, MESH: Treatment Outcome, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: MAP Kinase Signaling System, MESH: Adenocarcinoma, MESH: Adult, lung adenocarcinoma, MESH: Male, MESH: Drug Resistance, Neoplasm, respiratory tract diseases, MESH: Lung Neoplasms, MESH: Quinazolines, MESH: Tumor Markers, Biological, MESH: Antineoplastic Agents, amphiregulin, MESH: Female, MESH: DNA-Binding Proteins
Abstract

International audience; The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non-mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component.

Published
2011
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18. Phosphorylation of histone H3 serine 10 in early mouse embryos: active phosphorylation at late S phase and differential effects of ZM447439 on first two embryonic mitoses

Author

Ewa Borsuk, Jacek Z. Kubiak, Maciej Meglicki, Michał Pasternak, Marta Teperek-Tkacz, Department of Embryology [Warsaw], Institute of Zoology [Warsaw], Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW)-Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé

Subjects
Male, Cell Cycle Proteins, S Phase, Histones, chemistry.chemical_compound, Mice, MESH: Benzamides, 0302 clinical medicine, Aurora Kinases, Serine, Aurora Kinase B, MESH: Animals, Phosphorylation, Kinetochores, MESH: Telophase, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Anaphase, Aurora Kinase A, MESH: Histones, 0303 health sciences, MESH: S Phase, ZM447439, Cell biology, Spindle checkpoint, MESH: Quinazolines, 030220 oncology & carcinogenesis, Benzamides, Mad2 Proteins, embryonic structures, Female, Aurora B kinase, Mitosis, Spindle Apparatus, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Protein Serine-Threonine Kinases, MESH: Anaphase, MESH: G1 Phase, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, MESH: Cell Cycle Proteins, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Animals, Telophase, MESH: Serine, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Mitotic Spindle Apparatus, MESH: Phosphorylation, MESH: Kinetochores, G1 Phase, MESH: Embryo, Mammalian, Cell Biology, MESH: Mitosis, Embryo, Mammalian, Molecular biology, MESH: Male, enzymes and coenzymes (carbohydrates), chemistry, Quinazolines, Multipolar spindles, MESH: Female, Developmental Biology
Abstract

International audience; Cell division in mammalian cells is regulated by Aurora kinases. The activity of Aurora A is indispensable for correct function of centrosomes and proper spindle formation, while Aurora B for chromosome biorientation and separation. Aurora B is also responsible for the phosphorylation of histone H3 serine 10 (H3S10Ph) from G2 to metaphase. Data concerning the Aurora B activity and H3S10Ph in embryonic cells are limited to primordial and maturing oocytes and advanced pronuclei in zygotes. In the present study we have analyzed H3S10Ph in 1- and 2-cell mouse embryos. We show that H3S10 remains phosphorylated at anaphase and telophase of the second meiotic division, as well as during the anaphase and telophase of the first and second embryonic mitoses. At late G1 H3S10 is dephosphorylated and subsequently phosphorylated de novo at late S phase of the first and second cell cycle. These results show that the H3S10 phosphorylation/dephosphorylation cycle in embryonic cells is different than in somatic cells. The behaviour of thymocyte G0 nuclei introduced into ovulated oocytes and early 1-cell parthenogenotes confirms that kinases responsible for de novo H3S10 phosphorylation, most probably Aurora B, are active until G1 of the first cell cycle of mouse embryo. The inhibition of Aurora kinases by ZM447439 caused abnormalities both in the first and second mitoses. However, the disturbances in each division differed, suggesting important differences in the control of these mitoses. In ZM447439-treated mitotic zygotes Mad2 protein remained continuously present on kinetochores, what confirmed that spindle checkpoint remained active.

Published
2010
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19. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer

Author

Cristina Oliva, M. John Kennedy, Gilles Romieu, Xavier Pivot, Michael F. Press, J. Maltzman, S. Stein, Stephen S. Johnston, L. O'Rourke, Henry L. Gomez, Mikhail Lichinitser, A. Florance, John Pippen, Alexey Manikhas, Saeed Sadeghi, Véronique Diéras, Mark D. Pegram, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])

Subjects
Oncology, MESH: Carcinoma, Cancer Research, Receptor, ErbB-2, Kaplan-Meier Estimate, MESH: Risk Assessment, MESH: Dose-Response Relationship, Drug, MESH: Proportional Hazards Models, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, MESH: Double-Blind Method, MESH: Kaplan-Meiers Estimate, skin and connective tissue diseases, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Letrozole, MESH: Maximum Tolerated Dose, MESH: Neoplasm Staging, Middle Aged, MESH: Antineoplastic Agents, Hormonal, Prognosis, Metastatic breast cancer, MESH: Nitriles, 3. Good health, Postmenopause, MESH: Quinazolines, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Receptors, Estrogen, MESH: Receptor, erbB-2, 030220 oncology & carcinogenesis, MESH: Survival Analysis, MESH: Receptors, Estrogen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Receptors, Progesterone, MESH: Postmenopause, medicine.drug, Adult, MESH: Receptors, Progesterone, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Maximum Tolerated Dose, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Population, Breast Neoplasms, MESH: Drug Administration Schedule, Lapatinib, Risk Assessment, Disease-Free Survival, Drug Administration Schedule, MESH: Prognosis, 03 medical and health sciences, Breast cancer, Double-Blind Method, Internal medicine, Nitriles, medicine, Biomarkers, Tumor, Humans, Neoplasm Invasiveness, education, 030304 developmental biology, Aged, Neoplasm Staging, Proportional Hazards Models, Aromatase inhibitor, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Carcinoma, MESH: Adult, MESH: Neoplasm Invasiveness, Triazoles, Antiestrogen, medicine.disease, Survival Analysis, Endocrinology, MESH: Triazoles, MESH: Tumor Markers, Biological, MESH: Disease-Free Survival, Quinazolines, business, MESH: Female, Tamoxifen, MESH: Breast Neoplasms
Abstract

PurposeCross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) –positive metastatic breast cancer (MBC).Patients and MethodsPostmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population.ResultsIn HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease ≥ 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.ConclusionThis trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Published
2009
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20. [Targeted therapy for locally advanced and/or metastatic bladder cancer]

Author

Wallerand , H., Robert , G., Bernhard , J.-C., Ravaud , A., Ferrière , J.-M., Service d'urologie, andrologie et transplantation rénale, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'oncologie médicale, CHU Bordeaux [Bordeaux], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Signal Transduction, Pyridines, MESH : Piperidines, Angiogenesis Inhibitors, MESH : Randomized Controlled Trials as Topic, MESH: Antibodies, Monoclonal, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Piperidines, MESH : Quinazolines, MESH: Protein Kinase Inhibitors, MESH : Immunosuppressive Agents, MESH: Angiogenesis Inhibitors, Randomized Controlled Trials as Topic, Antibiotics, Antineoplastic, Antibodies, Monoclonal, Gefitinib, MESH : Antibiotics, Antineoplastic, MESH: Urinary Bladder Neoplasms, Bevacizumab, MESH: Quinazolines, MESH : Antineoplastic Agents, MESH: Piperidines, MESH : Urinary Bladder Neoplasms, MESH : Antibodies, Monoclonal, Disease Progression, MESH : Targeted Gene Repair, MESH: Disease Progression, MESH: Immunosuppressive Agents, MESH : Mutation, MESH : Gene Therapy, Immunosuppressive Agents, Signal Transduction, Targeted Gene Repair, MESH: Mutation, MESH : Pyridines, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Erlotinib Hydrochloride, MESH : Angiogenesis Inhibitors, Humans, MESH: Antibiotics, Antineoplastic, Protein Kinase Inhibitors, Sirolimus, MESH : Signal Transduction, MESH: Humans, MESH : Sirolimus, MESH: Pyridines, MESH : Humans, Genetic Therapy, MESH : Disease Progression, Trastuzumab, MESH : Protein Kinase Inhibitors, MESH: Randomized Controlled Trials as Topic, Urinary Bladder Neoplasms, Mutation, Quinazolines, MESH: Antineoplastic Agents, MESH: Sirolimus, MESH: Gene Therapy, MESH: Targeted Gene Repair
Abstract

International audience; Cancer is a complex disease characterized by a multitude of molecular and genetic abnormalities affecting cell proliferation and differentiation, apoptosis, and mobility (invasion). Each of these alterations represents a potential target for the development of targeted therapy. These new therapies inhibit cell growth and are said to be "cytostatic" in contrast with conventional "cytotoxic" chemotherapy. As a result of a better understanding of the molecular biology of bladder cancers, various signalling pathways involved in both carcinogenesis and tumour progression have been defined, and some of the key molecules in these pathways have been isolated and can be used as prognostic markers and as potential therapeutic targets. Locally advanced, and/or metastatic bladder cancer, is characterized by mutations of the p53 and retinoblastoma (Rb) genes, regulators of the cell cycle, which interact with the Ras-mitogen activated protein kinase (MPAK) transduction pathway. Overexpression of tyrosine kinase receptors, including EGFR, VEFGR and HER2/neu, is correlated with tumour progression and activation of the phosphatidyl-inositol-3 kinase (PI-3K) pathway is involved in tumour invasion and inhibition of apoptosis. Due to their molecular heterogeneity, optimal targeted therapy of bladder cancers will require the combined use of several molecules. Modulation of signalling pathways by these new molecules can restore chemosensitivity to cytotoxic drugs, which can then be associated with targeted therapy.

Published
2008
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21. Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?

Author

Julien Taieb, Pierre Laurent-Puig, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), 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 Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Cancer Research, MESH: Clinical Trials as Topic, medicine.medical_treatment, MESH: Receptor, Epidermal Growth Factor, Targeted therapy, 03 medical and health sciences, Erlotinib Hydrochloride, 0302 clinical medicine, MESH : Quinazolines, MESH : Receptor, Epidermal Growth Factor, Pancreatic cancer, medicine, MESH: Protein Kinase Inhibitors, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Clinical Trials as Topic, MESH: Humans, business.industry, MESH : Humans, MESH: Research Design, MESH : Protein Kinase Inhibitors, MESH : Research Design, medicine.disease, 3. Good health, MESH : Clinical Trials as Topic, ErbB Receptors, Pancreatic Neoplasms, MESH: Quinazolines, Oncology, Research Design, 030220 oncology & carcinogenesis, Immunology, Cancer research, Quinazolines, Pancreatic carcinogenesis, MESH: Pancreatic Neoplasms, business, MESH : Pancreatic Neoplasms
Abstract

PURPOSE OF REVIEW: The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients. RECENT FINDINGS: Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-kappaB or can directly turn down Ras. SUMMARY: The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival.

Published
2008
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22. [Economic impact of second- and third-line erlotinib treatment of non small-cell lung cancer]

Author

C, Chouaid, A, Moser, C, Coudray-Omnès, A, Vergnenègre, Annesi-Maesano, Isabella, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), C Chouaid, Moser A, C-Omnès Coudray, and SCHILLER A .

Subjects
Adult, Male, Lung Neoplasms, MESH: Ambulatory Care, Cohort Studies, Erlotinib Hydrochloride, MESH: Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Ambulatory Care, Humans, MESH: Protein Kinase Inhibitors, MESH: Drug Utilization, Protein Kinase Inhibitors, MESH: Antiemetics, MESH: Cohort Studies, Aged, Aged, 80 and over, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: Adult, Middle Aged, Drug Utilization, MESH: Male, MESH: Lung Neoplasms, respiratory tract diseases, MESH: France, MESH: Quinazolines, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Quinazolines, Antiemetics, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

International audience; OBJECTIVE: This study examined care consumption and management costs among patients who received second- or third-line oral erlotinib therapy for non small-cell lung cancer (NSCLC). METHODS: The study involved two observational cohorts of NSCLC second- or third-line treated patients. In the first, patients received IV chemotherapy alone (233 patients), while patients in the second cohort, received oral erlotinib (166 patients). Only direct costs were taken into account. The analysis adopted the payer's perspective. RESULTS: The treatments lasted a similar length in the second- line setting (respectively 94,5+/-67,5 and 105+/-79,4 days for the IV and erlotinib cohorts) but was significantly longer in the erlotinib cohort during third-line therapy (76.6+/-96.5 versus and 114.4+/-74.5 days, p

Published
2008

23. Antifolate screening using yeast expressing Plasmodium vivax dihydrofolate reductase and in vitro drug susceptibility assay for Plasmodium falciparum

Author

Jeanne Ngogang Yonkeu, Ruth Zelikson, Joseph Allico Djaman, Andre Rosowsky, Liselotte Yimga Djapa, Leonardo K. Basco, André Mazabraud, Monique Bolotin-Fukuhara, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium vivax, Mutant, Drug resistance, MESH: Tetrahydrofolate Dehydrogenase, yeast, MESH: Parasitic Sensitivity Tests, chemistry.chemical_compound, 0302 clinical medicine, Parasitic Sensitivity Tests, Dihydrofolate reductase, MESH: Animals, MESH: Plasmodium falciparum, MESH: Inhibitory Concentration 50, 0303 health sciences, biology, antifolate drugs, MESH: Saccharomyces cerevisiae, 3. Good health, MESH: Plasmodium vivax, MESH: Quinazolines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Antifolate, MESH: Mutation, Plasmodium falciparum, 030231 tropical medicine, Saccharomyces cerevisiae, malaria, Plasmodium falciparum in vitro culture, Inhibitory Concentration 50, 03 medical and health sciences, parasitic diseases, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, 030304 developmental biology, MESH: Folic Acid Antagonists, drug resistance, biology.organism_classification, Virology, Tetrahydrofolate Dehydrogenase, chemistry, Mutation, Quinazolines, biology.protein, Folic Acid Antagonists, Parasitology
Abstract

The presence of homologous point mutations in the dhfr gene in Plasmodium vivax and Plasmodium falciparum is associated with resistance to antifolate drugs. The spread of antifolate resistance encouraged research for novel antifolate drugs active against both wild-type and dhfr-mutant strains of malaria parasites. Because P. vivax cannot be easily maintained in culture, we transformed a Saccharomyces cerevisiae DHFR-deleted mutant to express wild-type P. vivax dhfr gene and its mutant forms. Twenty-five dicyclic and tricyclic 2,4-diaminopyrimidine derivatives were screened. Six quinazoline compounds showed selective inhibition of yeast transformants expressing P. vivax dhfr genes. The 50% inhibitory concentration (IC50) of these six compounds was determined against field isolates of P. falciparum. Our results suggest that a close relationship between the yeast assay based on expression of P. vivax dhfr genes and the in vitro test using P. falciparum parasites in culture is a promising initial step for drug screening.

Published
2007
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24. Economic impact of gefitinib for refractory non-small-cell lung cancer: a Markov model-based analysis

Author

Maurice Pérol, Gilles Robinet, Alain Vergnenegre, Isabelle Monnet, Pierre Fournel, Christos Chouaid, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie 93, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département d'Oncologie médicale, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)

Subjects
Male, Oncology, Lung Neoplasms, Indirect costs, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, MESH: Drug Costs, 030212 general & internal medicine, health care economics and organizations, MESH: Aged, MESH: Middle Aged, Gefitinib, General Medicine, Middle Aged, Markov Chains, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, MESH: Survival Analysis, Cohort, Costs and Cost Analysis, Female, Non small cell, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, Markov model, MESH: Costs and Cost Analysis, Drug Costs, 03 medical and health sciences, Refractory, MESH: Markov Chains, Internal medicine, medicine, Humans, Target therapy, Lung cancer, neoplasms, Aged, MESH: Humans, business.industry, medicine.disease, Survival Analysis, MESH: Male, Surgery, respiratory tract diseases, MESH: Lung Neoplasms, Quinazolines, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

International audience; UNLABELLED: Few data are available on the economics of target therapy or refractory non-small-cell lung cancer (NSCLC). OBJECTIVE: To determine the mean global management costs (MC) per patient treated with gefitinib for NSCLC, and the costs of the different management phases. METHOD: A Markov approach was used to model treatment costs in a cohort of 106 patients treated with gefitinib as part of a compassionate-use program (third-line treatment) in six public-sector teaching hospitals. The economic analysis adopted the health care payer's perspective, and only direct costs were taken into account. RESULTS: The mean duration of gefitinib treatment was 4.6 +/- 5.8 months (1-29 months); median survival was 4 months, 1-year and 2-year survival rates were 12.3% and 4.7%, respectively. The mean total management cost was 39,979 euros +/- 20,279. The model showed that first- and second-line treatments accounted for respectively 29.5% and 44.1% of this cost, while gefitinib periods represented 10.7%, periods of remission 1.25%, and terminal care 14.5%. A sensitivity analysis showed that the price of gefitinib had little influence on the total cost. CONCLUSION: The cost of third-line gefitinib therapy for NSCLC appears acceptable from the healthcare payer's perspective, but this needs to be confirmed in dedicated cost-effectiveness studies.

Published
2007
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25. Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening

Author

Jean-Yves Springael, Didier Rognan, Marc Parmentier, Jean-Luc Galzi, Esther Kellenberger, Muriel Hachet-Haas, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Faculteit Toegepaste Economische Wetenschappen (TEW), University of Antwerp (UA), Agence Universitaire de la Francophonie (AUF), Récepteurs et protéines membranaires (RPM), Centre National de la Recherche Scientifique (CNRS), Pharmacochimie de la communication cellulaire (PCC), Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université de Bruxelles, Université libre de Bruxelles (ULB), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)

Subjects
Models, Molecular, Pyrrolidines, Chemokine receptor CCR5, MESH: Sequence Homology, Amino Acid, MESH: Piperazines, Quantitative Structure-Activity Relationship, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Amino Acid Sequence, MESH: Receptors, CCR5, 01 natural sciences, Piperazines, MESH: Protein Structure, Tertiary, Piperidines, Drug Discovery, Receptor, 0303 health sciences, MESH: Quantitative Structure-Activity Relationship, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, Chemistry, virus diseases, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Pyridazines, MESH: Quinazolines, MESH: Piperidines, CCR5 Receptor Antagonists, Molecular Medicine, Pharmacophore, [CHIM.CHEM]Chemical Sciences/Cheminformatics, MESH: Models, Molecular, Agonist, Receptors, CCR5, Stereochemistry, medicine.drug_class, In silico, MESH: Molecular Structure, Molecular Sequence Data, CCR5 receptor antagonist, Computational biology, 03 medical and health sciences, MESH: Pyridazines, medicine, Amino Acid Sequence, 030304 developmental biology, Virtual screening, MESH: Molecular Sequence Data, MESH: Pyrrolidines, Sequence Homology, Amino Acid, Triazoles, 0104 chemical sciences, Protein Structure, Tertiary, 010404 medicinal & biomolecular chemistry, MESH: Triazoles, Docking (molecular), biology.protein, Quinazolines
Abstract

International audience; A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

Published
2007
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26. Characterization and effects on cAMP accumulation of adrenomedullin and calcitonin gene-related peptide (CGRP) receptors in dissociated rat spinal cord cell culture

Author

Takhshid, Mohammad A, Poyner, David R, Chabot, Jean-Guy, Fournier, Alain, Ma, Weiya, Zheng, Wen-Hua, Owji, Ali A, Quirion, Remi, Fasa Medical School, Shiraz University of Medical Sciences [Iran] (SUMS), School of Life and Health Sciences, Aston University [Birmingham], Department of Psychiatry [Montréal], McGill University = Université McGill [Montréal, Canada], Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Biochemistry, and This research was supported by the Canadian Institutes of Health Research (CIHR) to R. Quirion. D.R. Poyner was supported by the British Heart Foundation (PG/03/079/15728).

Subjects
MESH: Rats, Calcitonin Gene-Related Peptide, MESH: Piperazines, MESH: Receptors, Adrenomedullin, MESH: Binding, Competitive, MESH: Rats, Sprague-Dawley, MESH: Receptors, G-Protein-Coupled, Binding, Competitive, Piperazines, Receptors, G-Protein-Coupled, MESH: Spinal Cord, Rats, Sprague-Dawley, Adrenomedullin, Cyclic AMP, MESH: Calcitonin Gene-Related Peptide, Animals, MESH: Animals, Receptors, Adrenomedullin, MESH: Peptide Fragments, MESH: Cyclic AMP, Cells, Cultured, Binding Sites, MESH: Immunohistochemistry, Immunohistochemistry, MESH: Adrenomedullin, Peptide Fragments, Rats, MESH: Quinazolines, MESH: Binding Sites, Spinal Cord, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Papers, Quinazolines, Female, MESH: Receptors, Calcitonin Gene-Related Peptide, MESH: Female, MESH: Cells, Cultured, Receptors, Calcitonin Gene-Related Peptide
Abstract

International audience; Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) have structural similarities, interact with each others receptors (calcitonin receptor-like receptor (CLR)/receptor-activity-modifying proteins (RAMPs)) and show overlapping biological activities. AM and CGRP receptors are chiefly coupled to cAMP production. In this study, a method of primary dissociated cell culture was used to investigate the presence of AM and CGRP receptors and their effects on cAMP production in embryonic spinal cord cells. Both neuronal and non-neuronal CLR immunopositive cells were present in our model. High affinity, specific [(125)I]-AM binding sites (K(d) 79 +/- 9 pM and B(max) 571 +/- 34 fmol mg(-1) protein) were more abundant than specific [(125)I]-CGRP binding sites (K(d) 12 +/- 0.7 pM and B(max) 32 +/- 2 fmol mg(-1) protein) in embryonic spinal cord cells. Specific [(125)I]-AM binding was competed by related molecules with a ligand selectivity profile of rAM > hAM(22-52) > rCGRPalpha > CGRP(8-37) > [r-(r(*),s(*))]-N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-,1-piperidinecarboxamide (BIBN4096BS). Specific [(125)I]-CGRP binding was competed by rCGRPalpha > rAM > or = CGRP(8-37) > or = BIBN4096BS > hAM(22-52). Cellular levels of cAMP were increased by AM (pEC(50) 10.2 +/- 0.2) and less potently by rCGRPalpha (pEC(50) 8.9 +/- 0.4). rCGRPalpha-induced cAMP accumulation was effectively inhibited by CGRP(8-37) (pA(2) 7.63 +/- 0.44) and hAM(22-52) (pA(2) 6.18 +/- 0.21) while AM-stimulation of cAMP levels was inhibited by CGRP(8-37) (pA(2) 7.41+/- 0.15) and AM(22-52) (pA(2) 7.26 +/- 0.18). BIBN4096BS only antagonized the effects of CGRP (pA(2) 8.40 +/- 0.30) on cAMP accumulation. These pharmacological profiles suggest that effects of CGRP are mediated by the CGRP(1) (CLR/RAMP1) receptor in our model while those of AM are related to the activation of the AM(1) (CLR/RAMP2) receptor subtype.

Published
2006
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27. Evaluation of antiangiogenic treatment effects on tumors' microcirculation by Bayesian physiological pharmacokinetic modeling and magnetic resonance imaging

Author

Bertrand Bessoud, Nathalie Siauve, Frédéric Y. Bois, Daniel Balvay, Charles-André Cuénod, Céline Brochot, Saidi, Vanessa, Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire de Recherche en Imagerie (LRI), Faculté de Necker, Service de Radiologie, Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, Blood pool agent, Pathology, Contrast Media, 030218 nuclear medicine & medical imaging, MESH: Magnetic Resonance Imaging, Mice, 0302 clinical medicine, Heterocyclic Compounds, Neoplasms, MESH: Microcirculation, Medicine, MESH: Animals, MESH: Neoplasms, medicine.diagnostic_test, Neovascularization, Pathologic, Magnetic Resonance Imaging, MESH: Quinazolines, Dynamic contrast-enhanced MRI, Arterial blood, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Physiologically based pharmacokinetic modelling, Biodistribution, medicine.medical_specialty, MESH: Heterocyclic Compounds, MESH: Bayes Theorem, Biomedical Engineering, Biophysics, Mice, Nude, Microcirculation, 03 medical and health sciences, Pharmacokinetics, MESH: Contrast Media, Organometallic Compounds, MESH: Mice, Nude, Animals, Radiology, Nuclear Medicine and imaging, MESH: Mice, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Magnetic resonance imaging, Bayes Theorem, MESH: Organometallic Compounds, Triazoles, Xenograft Model Antitumor Assays, MESH: Male, MESH: Triazoles, Quinazolines, business, MESH: Neovascularization, Pathologic, 030217 neurology & neurosurgery, Neoplasm Transplantation, MESH: Neoplasm Transplantation, MESH: X
Abstract

International audience; A physiological pharmacokinetic (PBPK) model was used to estimate tumor microcirculation in nude mice with a grafted tumor. The kinetics of a rapid clearance blood pool agent, Vistarem, were investigated by dynamic MRI after bolus administration. Signal enhancements were recorded in arterial blood and in tumor tissue. To analyze these data, we developed a whole-body mathematical model of the agent's biodistribution using physiological parameters. The model included six compartments: arterial and venous plasma, tumor (split into capillaries and interstitium), and the rest of the body (also split into capillaries and interstitium). As an application, changes in tumor microcirculation parameters were evaluated in mice receiving either an antiangiogenic treatment (ZD4190) or a placebo. The analysis was performed in a Bayesian framework, and the model was fitted to experimental data using Markov Chain Monte Carlo techniques. Results showed a significant difference in tumor microcirculation between the two groups of mice when the microcirculation parameters are considered together. This whole-body physiological model enables to analyze jointly data in tumor tissue and in arterial blood. This leads to accurate estimates of microcirculation parameters and the evaluation of their uncertainty.

Published
2006
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28. Synthesis of the PPARbeta/delta-selective agonist GW501516 and C4-thiazole-substituted analogs

Author

Hinrich Gronemeyer, Beatriz Iglesias, Claudine Gaudon, Pierre Germain, Angel R. de Lera, Raquel Pereira, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Time Factors, Transcription, Genetic, Chemistry, Pharmaceutical, Clinical Biochemistry, Pharmaceutical Science, MESH: Drug Design, Ligands, 01 natural sciences, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Suzuki reaction, Genes, Reporter, Drug Discovery, Hydroxybenzoates, MESH: Ligands, PPAR delta, Promoter Regions, Genetic, chemistry.chemical_classification, MESH: Models, Chemical, Lipids, 3. Good health, Globins, MESH: Promoter Regions (Genetics), MESH: Quinazolines, Genetic Techniques, Molecular Medicine, MESH: Palladium, Palladium, Agonist, Transcriptional Activation, MESH: PPAR-beta, medicine.drug_class, Stereochemistry, Carboxylic acid, MESH: Thiazoles, Ether, MESH: Hydroxybenzoic Acids, 010402 general chemistry, Catalysis, GW501516, Cell Line, MESH: Chemistry, Pharmaceutical, mental disorders, medicine, MESH: Globins, Humans, MESH: PPAR delta, Thiazole, Molecular Biology, PPAR-beta, MESH: Humans, 010405 organic chemistry, MESH: Transcription, Genetic, Organic Chemistry, MESH: Time Factors, MESH: Genes, Reporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Catalysis, MESH: Lipids, 0104 chemical sciences, Stille reaction, MESH: Cell Line, MESH: Hela Cells, Thiazoles, MESH: Genetic Techniques, chemistry, Models, Chemical, MESH: Trans-Activation (Genetics), Drug Design, Quinazolines, HeLa Cells
Abstract

Sequential, position-selective, Pd-catalyzed cross-coupling reactions of 2,4-dibromo-5-hydroxymethylthiazole provided the scaffold for the synthesis of GW501516, the most potent PPARbeta/delta agonist yet described, and equally selective analogs at the thiazole-C4 position.

Published
2006
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29. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors

Author

Thierry Besson, Jean-Marie Piot, Olivier Lozach, Laurent Meijer, Mélina Blairvacq, Alexandra Testard, Valérie Thiéry, Laurent Picot, Laurence Murillo, LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cell Line, Tumor, MESH: Molecular Structure, Drug Evaluation, Preclinical, MESH: Microwaves, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Structure-Activity Relationship, MESH: Structure-Activity Relationship, Cyclin-dependent kinase, GSK-3, Cell Line, Tumor, MESH: Cell Proliferation, Drug Discovery, Structure–activity relationship, Humans, Enzyme Inhibitors, Microwaves, 030304 developmental biology, Cell Proliferation, MESH: Glycogen Synthase Kinase 3, Pharmacology, 0303 health sciences, MESH: Humans, biology, Molecular Structure, 010405 organic chemistry, Kinase, Chemistry, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Medicine, Cyclin-Dependent Kinases, 0104 chemical sciences, 3. Good health, MESH: Quinazolines, MESH: Cyclin-Dependent Kinases, Biochemistry, Cell culture, MESH: Enzyme Inhibitors, biology.protein, Quinazolines, MESH: Drug Evaluation, Preclinical, Lead compound
Abstract

International audience; The microwave-assisted synthesis of a family of 2,8-substituted thiazoloquinazolinones is described. The preliminary evaluation of the antiproliferative activity and the capacity of these molecules to inhibit CDKs and GSK-3 are reported. A lead compound was identified, constituting a scaffold from which more potent inhibitors could be designed.

Published
2005
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30. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells

Author

Geneviève Fiol, Dirk Hose, Friedrich W. Cremer, Veronique Grau, Jean François Rossi, Bernard Klein, Hartmut Goldschmidt, Marion Moos, Eric Jourdan, Jérôme Moreaux, Karène Mahtouk, Thierry Rème, Michel Jourdan, Marion Baudard, Marc-Steffen Raab, John De Vos, Frei, Monique, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Service de médecine interne B, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Institut für Humangenetik, and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)

Subjects
Cancer Research, medicine.medical_treatment, Apoptosis, MESH: Multiple Myeloma, medicine.disease_cause, ErbB Receptors, 0302 clinical medicine, Multiple myeloma, Oligonucleotide Array Sequence Analysis, 0303 health sciences, MESH: Plasma Cells, Reverse Transcriptase Polymerase Chain Reaction, MESH: Bone Marrow Cells, Gefitinib, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Multiple Myeloma, EGF Family of Proteins, Stromal cell, Plasma Cells, MESH: Glycoproteins, Antineoplastic Agents, Bone Marrow Cells, Biology, Amphiregulin, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, ErbB, MESH: Cell Proliferation, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Intercellular Signaling Peptides and Proteins, Molecular Biology, 030304 developmental biology, Cell Proliferation, Glycoproteins, MESH: Humans, Cell growth, Growth factor, Gene Expression Profiling, MESH: Apoptosis, medicine.disease, MESH: Oligonucleotide Array Sequence Analysis, Cancer research, Quinazolines, MESH: Antineoplastic Agents, Carcinogenesis
Abstract

International audience; A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.

Published
2005
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31. Autocrine activation of adenosine A1 receptors blocks D1A but not D1B dopamine receptor desensitization

Author

Le Crom, Stéphane, Prou, Delphine, Vernier, Philippe, Développement, évolution et plasticité du système nerveux (DEPSN), Centre National de la Recherche Scientifique (CNRS), and Institut de Neurobiologie Alfred Fessard (INAF)

Subjects
Adenosine, Time Factors, Phosphodiesterase Inhibitors, Transfection, MESH: Receptors, Dopamine D1, MESH: Phosphodiesterase Inhibitors, Cell Line, MESH: Receptors, Dopamine D5, Mice, Cyclic AMP, Animals, Receptors, Dopamine D5, MESH: Animals, MESH: Receptors, Purinergic P1, MESH: Dopamine Agonists, MESH: Mice, MESH: Cyclic AMP, Receptors, Dopamine D1, MESH: Transfection, MESH: Time Factors, Receptors, Purinergic P1, Fibroblasts, Triazoles, MESH: Adenosine, MESH: Cell Line, MESH: COS Cells, Autocrine Communication, MESH: Quinazolines, MESH: Triazoles, MESH: Fibroblasts, Xanthines, COS Cells, Dopamine Agonists, Quinazolines, MESH: Xanthines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Autocrine Communication
Abstract

Adenosine is known to modulate dopamine responses in several brain areas. Here, we show that tonic activation of adenosine receptors is able to impede desensitization of D1 dopamine receptors. As measured by cAMP accumulation in transfected COS-7 cells, long-term exposure to dopamine agonists promoted desensitization of D1B receptor but not that of D1A receptor. The inability of D1A receptor to desensitize was a result of the adenosine present in culture medium acting through activation of adenosine A1 receptors. Cell incubation with either adenosine deaminase, CGS-15943, a generic adenosine receptor antagonist, or the A1 antagonist DPCPX restored the long-term desensitization time-course of D1A receptors. In Ltk cells stably expressing A1 adenosine receptors and D1A dopamine receptors, pre-treatment of cells with R(-)-PIA, a full A1 receptor agonist, did not significantly inhibit the acute increase in cAMP levels induced by D1 receptor agonists, but blocked desensitization of D1A receptors. However, simultaneous activation of A1 and D1A receptors promoted a delayed D1A receptor desensitization. This suggests that functional interaction between A1 and D1A receptors may depend on the activation kinetics of components regulating D1 receptor responses, acting differentially on D1A and D1B receptors.

Published
2002
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