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  1. AU="Calvet, Loreley"
  2. AU="Rui Pinto"
  3. AU="Feret, Geoff"
  4. AU="Sherrill-Mix, Scott"
  5. AU="Eleanor Eaton"
  6. AU="Latour, Corine H M"
  7. AU="Radetic, Mark"
  8. AU="James Jensen"
  9. AU="McFalls, Jeanne"
  10. AU="Sylvain Sebert"

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  1. Artikel: TEAD Inhibitors Sensitize KRAS

    Tammaccaro, Salvina Laura / Prigent, Philippe / Le Bail, Jean-Christophe / Dos-Santos, Odette / Dassencourt, Laurent / Eskandar, Myriam / Buzy, Armelle / Venier, Olivier / Guillemot, Jean-Claude / Veeranagouda, Yaligara / Didier, Michel / Spanakis, Emmanuel / Kanno, Tokuwa / Cesaroni, Matteo / Mathieu, Stephane / Canard, Luc / Casse, Alhassan / Windenberger, Fanny / Calvet, Loreley /
    Noblet, Laurence / Sidhu, Sukhvinder / Debussche, Laurent / Moll, Jurgen / Valtingojer, Iris

    Pharmaceuticals (Basel, Switzerland)

    2023  Band 16, Heft 4

    Abstract: ... ...

    Abstract KRAS
    Sprache Englisch
    Erscheinungsdatum 2023-04-06
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16040553
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: YAP1 is essential for malignant mesothelioma tumor maintenance.

    Calvet, Loreley / Dos-Santos, Odette / Spanakis, Emmanuel / Jean-Baptiste, Véronique / Le Bail, Jean-Christophe / Buzy, Armelle / Paul, Pascal / Henry, Christophe / Valence, Sandrine / Dib, Colette / Pollard, Jack / Sidhu, Sukhvinder / Moll, Jürgen / Debussche, Laurent / Valtingojer, Iris

    BMC cancer

    2022  Band 22, Heft 1, Seite(n) 639

    Abstract: Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are ... ...

    Abstract Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.
    Mesh-Begriff(e) Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Mesothelioma/pathology ; Mesothelioma, Malignant ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; YAP-Signaling Proteins
    Chemische Substanzen Phosphoproteins ; YAP-Signaling Proteins ; YAP1 protein, human
    Sprache Englisch
    Erscheinungsdatum 2022-06-10
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2041352-X
    ISSN 1471-2407 ; 1471-2407
    ISSN (online) 1471-2407
    ISSN 1471-2407
    DOI 10.1186/s12885-022-09686-y
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors.

    Vrignaud, Patricia / Sémiond, Dorothée / Lejeune, Pascale / Bouchard, Hervé / Calvet, Loreley / Combeau, Cecile / Riou, Jean-François / Commerçon, Alain / Lavelle, François / Bissery, Marie-Christine

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2013  Band 19, Heft 11, Seite(n) 2973–2983

    Abstract: Purpose: Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed ... ...

    Abstract Purpose: Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.
    Experimental design: Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.
    Results: In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013-0.414 μmol/L; docetaxel, 0.17-4.01 μmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).
    Conclusions: Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm ; Female ; Humans ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/pathology ; Mice ; Microtubule Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/pathology ; Protein Stability/drug effects ; Taxoids/administration & dosage ; Taxoids/pharmacokinetics ; Taxoids/pharmacology
    Chemische Substanzen Antineoplastic Agents ; Microtubule Proteins ; Taxoids ; docetaxel (15H5577CQD) ; cabazitaxel (51F690397J)
    Sprache Englisch
    Erscheinungsdatum 2013-06-01
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-12-3146
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.

    Wenzel, Silke C / Hoffmann, Holger / Zhang, Jidong / Debussche, Laurent / Haag-Richter, Sabine / Kurz, Michael / Nardi, Frederico / Lukat, Peer / Kochems, Irene / Tietgen, Heiko / Schummer, Dietmar / Nicolas, Jean-Paul / Calvet, Loreley / Czepczor, Valerie / Vrignaud, Patricia / Mühlenweg, Agnes / Pelzer, Stefan / Müller, Rolf / Brönstrup, Mark

    Angewandte Chemie (International ed. in English)

    2015  Band 54, Heft 51, Seite(n) 15560–15564

    Abstract: The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides ...

    Abstract The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
    Mesh-Begriff(e) Animals ; Area Under Curve ; Azepines/metabolism ; Azepines/pharmacokinetics ; Azepines/pharmacology ; Biological Products/metabolism ; Biological Products/pharmacokinetics ; Biological Products/pharmacology ; Female ; Half-Life ; Marine Biology ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Myxococcales/metabolism ; Porifera/metabolism ; Structure-Activity Relationship
    Chemische Substanzen Azepines ; Biological Products
    Sprache Englisch
    Erscheinungsdatum 2015-12-14
    Erscheinungsland Germany
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201508277
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer.

    Egile, Coumaran / Kenigsberg, Mireille / Delaisi, Christine / Bégassat, Françoise / Do-Vale, Véronique / Mestadier, Jessica / Bonche, Fabrice / Bénard, Tsiala / Nicolas, Jean-Paul / Valence, Sandrine / Lefranc, Céline / Francesconi, Elisa / Castell, Christelle / Lefebvre, Anne-Marie / Nemecek, Conception / Calvet, Loreley / Goulaouic, Hélène

    Molecular cancer therapeutics

    2014  Band 14, Heft 2, Seite(n) 384–394

    Abstract: Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative ... ...

    Abstract Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.
    Mesh-Begriff(e) Adenosine Triphosphate/pharmacology ; Administration, Intravenous ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Azoles/administration & dosage ; Azoles/chemistry ; Azoles/pharmacology ; Benzothiazoles/administration & dosage ; Benzothiazoles/chemistry ; Benzothiazoles/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Female ; Gene Amplification/drug effects ; HEK293 Cells ; Humans ; Mice, SCID ; Mutation/genetics ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Stomach Neoplasms/enzymology ; Stomach Neoplasms/pathology ; Urea/administration & dosage ; Urea/analogs & derivatives ; Urea/chemistry ; Urea/pharmacology
    Chemische Substanzen Antineoplastic Agents ; Azoles ; Benzothiazoles ; Protein Kinase Inhibitors ; SAR125844 ; Adenosine Triphosphate (8L70Q75FXE) ; Urea (8W8T17847W) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2014-12-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-14-0428
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

    Ugolini, Antonio / Kenigsberg, Mireille / Rak, Alexey / Vallée, Francois / Houtmann, Jacques / Lowinski, Maryse / Capdevila, Cécile / Khider, Jean / Albert, Eva / Martinet, Nathalie / Nemecek, Conception / Grapinet, Sandrine / Bacqué, Eric / Roesner, Manfred / Delaisi, Christine / Calvet, Loreley / Bonche, Fabrice / Semiond, Dorothée / Egile, Coumaran /
    Goulaouic, Hélène / Schio, Laurent

    Journal of medicinal chemistry

    2016  Band 59, Heft 15, Seite(n) 7066–7074

    Abstract: The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein ... ...

    Abstract The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.
    Mesh-Begriff(e) Animals ; Benzothiazoles/administration & dosage ; Benzothiazoles/chemistry ; Benzothiazoles/pharmacokinetics ; Benzothiazoles/pharmacology ; Cell Proliferation/drug effects ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Mice ; Models, Molecular ; Molecular Structure ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/metabolism ; Structure-Activity Relationship ; Urea/administration & dosage ; Urea/analogs & derivatives ; Urea/chemistry ; Urea/pharmacokinetics ; Urea/pharmacology
    Chemische Substanzen Benzothiazoles ; Protein Kinase Inhibitors ; SAR125844 ; Urea (8W8T17847W) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2016-08-11
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.6b00280
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Hefte anzeigen Standort:
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    Zs.MB 1: Hefte anzeigen

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  7. Artikel ; Online: Production of the Bengamide Class of Marine Natural Products in Myxobacteria

    Wenzel, Silke C / Hoffmann, Holger / Zhang, Jidong / Debussche, Laurent / Haag-Richter, Sabine / Kurz, Michael / Nardi, Frederico / Lukat, Peer / Kochems, Irene / Tietgen, Heiko / Schummer, Dietmar / Nicolas, Jean-Paul / Calvet, Loreley / Czepczor, Valerie / Vrignaud, Patricia / Mühlenweg, Agnes / Pelzer, Stefan / Müller, Rolf / Brönstrup, Mark

    Biosynthesis and Structure-Activity Relationships.

    2015  

    Abstract: The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides ...

    Abstract The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
    Sprache Englisch
    Erscheinungsdatum 2015-12-14
    Erscheinungsland de
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: Production of the Bengamide Class of Marine Natural Products in Myxobacteria

    Wenzel, Silke C / Hoffmann, Holger / Zhang, Jidong / Debussche, Laurent / Haag-Richter, Sabine / Kurz, Michael / Nardi, Frederico / Lukat, Peer / Kochems, Irene / Tietgen, Heiko / Schummer, Dietmar / Nicolas, Jean-Paul / Calvet, Loreley / Czepczor, Valerie / Vrignaud, Patricia / Mühlenweg, Agnes / Pelzer, Stefan / Müller, Rolf / Brönstrup, Mark

    Biosynthesis and Structure-Activity Relationships.

    2015  

    Abstract: The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides ...

    Abstract The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
    Sprache Englisch
    Erscheinungsdatum 2015-12-14
    Erscheinungsland de
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel ; Online: A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.

    Vecchione, Loredana / Gambino, Valentina / Raaijmakers, Jonne / Schlicker, Andreas / Fumagalli, Arianna / Russo, Mariangela / Villanueva, Alberto / Beerling, Evelyne / Bartolini, Alice / Mollevi, David G / El-Murr, Nizar / Chiron, Marielle / Calvet, Loreley / Nicolazzi, Céline / Combeau, Cécile / Henry, Christophe / Simon, Iris M / Tian, Sun / in 't Veld, Sjors /
    D'ario, Giovanni / Mainardi, Sara / Beijersbergen, Roderick L / Lieftink, Cor / Linn, Sabine / Rumpf-Kienzl, Cornelia / Delorenzi, Mauro / Wessels, Lodewyk / Salazar, Ramon / Di Nicolantonio, Federica / Bardelli, Alberto / van Rheenen, Jacco / Medema, René H / Tejpar, Sabine / Bernards, René

    Cell

    2016  Band 165, Heft 2, Seite(n) 317–330

    Abstract: BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based ... ...

    Abstract BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents, Phytogenic/administration & dosage ; Antineoplastic Agents, Phytogenic/pharmacology ; Cells, Cultured ; Colonic Neoplasms/classification ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Heterografts ; Humans ; Mice ; Mice, Nude ; Microtubules/drug effects ; Microtubules/metabolism ; Molecular Chaperones/genetics ; Neoplasm Transplantation ; Nuclear Pore Complex Proteins/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Vinblastine/administration & dosage ; Vinblastine/analogs & derivatives ; Vinblastine/pharmacology ; Vinorelbine
    Chemische Substanzen Antineoplastic Agents, Phytogenic ; Molecular Chaperones ; Nuclear Pore Complex Proteins ; ran-binding protein 2 ; Vinblastine (5V9KLZ54CY) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Vinorelbine (Q6C979R91Y)
    Sprache Englisch
    Erscheinungsdatum 2016-03-31
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2016.02.059
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel: In vivo treatment with CPT-11 leads to differentiation of neuroblastoma xenografts and topoisomerase I alterations.

    Santos, Alexandre / Calvet, Loreley / Terrier-Lacombe, Marie-Josee / Larsen, Annette / Bénard, Jean / Pondarré, Corinne / Aubert, Geneviève / Morizet, Jackie / Lavelle, François / Vassal, Gilles

    Cancer research

    2004  Band 64, Heft 9, Seite(n) 3223–3229

    Abstract: Topoisomerase I inhibitors, such as CPT-11, are potent anticancer drugs against neuroblastoma (NB). Differentiating agents, such as retinoids, improve the survival of children with metastatic NB. To characterize the biological effects associated with ... ...

    Abstract Topoisomerase I inhibitors, such as CPT-11, are potent anticancer drugs against neuroblastoma (NB). Differentiating agents, such as retinoids, improve the survival of children with metastatic NB. To characterize the biological effects associated with exposure to CPT-11 in vivo, athymic mice bearing a human NB xenograft, named IGR-NB8 and characterized as an immature NB with poor prognostic markers, were treated with CPT-11. Prolonged stable disease was observed, resulting in an overall tumor growth delay of 115 days. During treatment, tumors differentiated into ganglioneuroblastomas (GGNB), which reverted into an immature phenotype when treatment was discontinued. In contrast, 13-cis retinoic acid failed to induce differentiation of IGR-NB8 in vivo. Tumor differentiation was associated with decreased N-myc expression, induction of p73 expression in the perinuclear area and cytoplasm, and a dramatic 35-fold decrease in topoisomerase I (topo I) catalytic activity. The full-length Mr 100,000 topo I protein was present in both pre and post-treatment immature NB xenografts. In contrast, differentiated GGNBs did not contain the Mr 100,000 protein but an intense Mr 48,000 topo I fragment. Furthermore, redistribution of the Mr 48,000 and 68,000 forms to the cytoplasm was observed in differentiated tumors. The same pattern of topo I expression and catalytic activity was observed in NBs and GGNBs obtained from pediatric patients. Our data suggest that prolonged in vivo exposure to CPT-11 induces differentiation of NB xenografts, which is associated with truncation of the topo I enzyme, relocation of the degraded forms to the cytoplasm, and decreased catalytic activity.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Camptothecin/analogs & derivatives ; Camptothecin/pharmacology ; Cell Differentiation/drug effects ; Cell Division/drug effects ; Child ; Child, Preschool ; DNA Topoisomerases, Type I/metabolism ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Infant ; Infant, Newborn ; Irinotecan ; Male ; Mice ; Mice, Nude ; Neuroblastoma/drug therapy ; Neuroblastoma/enzymology ; Neuroblastoma/pathology ; Retinaldehyde/pharmacology ; Topoisomerase I Inhibitors ; Xenograft Model Antitumor Assays
    Chemische Substanzen Antineoplastic Agents, Phytogenic ; Enzyme Inhibitors ; Topoisomerase I Inhibitors ; 13-cis-retinal (472-86-6) ; Irinotecan (7673326042) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; Retinaldehyde (RR725D715M) ; Camptothecin (XT3Z54Z28A)
    Sprache Englisch
    Erscheinungsdatum 2004-04-26
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.can-03-2915
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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