26 results on '"Guida, Teresa"'
Search Results
2. Molecular Mechanism of 17-Allylamino-17-demethoxygeldanamycin (17-AAG)-induced AXL Receptor Tyrosine Kinase Degradation
- Author
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Krishnamoorthy, Gnana Prakasam, Guida, Teresa, Alfano, Luigi, Avilla, Elvira, Santoro, Massimo, Carlomagno, Francesca, and Melillo, Rosa Marina
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- 2013
- Full Text
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Catalog
3. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors
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Carlomagno, Francesca, Guida, Teresa, Anaganti, Suresh, Vecchio, Giancarlo, Fusco, Alfredo, Ryan, Anderson J, Billaud, Marc, and Santoro, Massimo
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- 2004
- Full Text
- View/download PDF
4. RET Is a Heat Shock Protein 90 (HSP90) Client Protein and Is Knocked Down upon HSP90 Pharmacological Block
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Alfano, Luigi, Guida, Teresa, Provitera, Livia, Vecchio, Giancarlo, Billaud, Marc, Santoro, Massimo, and Carlomagno, Francesca
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- 2010
5. BAY 43-9006 Inhibition of Oncogenic RET Mutants
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Carlomagno, Francesca, Anaganti, Suresh, Guida, Teresa, Salvatore, Giuliana, Troncone, Giancarlo, Wilhelm, Scott M., and Santoro, Massimo
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- 2006
6. Mitogenic Effects of the Up-Regulation of Minichromosome Maintenance Proteins in Anaplastic Thyroid Carcinoma
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Guida, Teresa, Salvatore, Giuliana, Faviana, Pinuccia, Giannini, Riccardo, Garcia-Rostan, Ginesa, Provitera, Livia, Basolo, Fulvio, Fusco, Alfredo, Carlomagno, Francesca, and Santoro, Massimo
- Published
- 2005
7. Efficient Inhibition of RET/Papillary Thyroid Carcinoma Oncogenic Kinases by 4-Amino-5-(4-Chloro-Phenyl)-7-(t-Butyl)Pyrazolo[3,4-d]Pyrimidine (PP2)
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Carlomagno, Francesca, Vitagliano, Donata, Guida, Teresa, Basolo, Fulvio, Castellone, Maria Domenica, Melillo, Rosa Marina, Fusco, Alfredo, and Santoro, Massimo
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- 2003
8. Phase II Study of mitoxantrone in association with desametasone in the treatment of hormone-refractory metastatic prostate cancer.
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Cartenì, Giacomo, Guida, Teresa, De Rosa, Patrizia, Esposito, Giovanni, Nicolella, Giampaolo, Panza, Nicola, Battista, Camillo, Biglietto, Maria, Chiurazzi, Bruno, Fariello, Annamaria, Petrizzi, Valeria Belsito, Germano, Domenico, Fiorentino, Roberto, Russo, Paola, and Guarrasi, Rosario more...
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- 2001
9. Cisplatin (CDDP), raltitrexed (Tomudex, TOM), levofolinic acid (LFA) and 5-fluorouracil (5-FU) versus CDDP, methotrexate (MTX), LFA, and 5-FU in locally advanced (LAD) or metastatic (M) head and neck cancer (HNC). A phase II randomized study.
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Caponigro, Francesco, Rosati, Gerardo, Avallone, Antonio, De Lucia, Luigi, Rivellini, Flavia, Guida, Teresa, Mantovani, Giovanni, Manzione, Luigi, Comella, Pasquale, and Comella, Giuseppe
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- 2000
10. A PHASE II RANDOMIZED STUDY OF CISPLATIN (CDDP), TOMUDEX (TOM), LEVOFOLINIC ACID (LFA) AND 5-FLUOROURACIL (5-FU) VERSUS CDDP, METHOTREXATE (MTX), LFA, AND 5-FU IN LOCALLY ADVANCED (LAD) OR METASTATIC (M) HEAD AND NECK CANCER (HNC).
- Author
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Caponigro, Francesco, Rosati, Gerardo, Avallone, Antonio, Budillon, Alfredo, Manzione, Luigi, De Lucia, Luigi, Rivellini, Flavia, Guida, Teresa, Mantovani, Giovanni, Comella, Pasquale, and Comella, Giuseppe more...
- Published
- 2000
11. NCOA4 inhibits initiation of DNA replication to maintain genome stability
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BELLELLI, ROBERTO, CASTELLONE, MARIA DOMENICA, GUIDA, TERESA, GRIECO, DOMENICO, COSTANZO, VINCENZO, FUSCO, ALFREDO, SANTORO, MASSIMO, CARLOMAGNO, Francesca, Annamaria Cirafici, Francesco Merolla, Livia Provitera, Roberto Limongello, Nina Dathan, Societa' Italiana di Cancerologia, Bellelli, Roberto, Castellone, MARIA DOMENICA, Guida, Teresa, Annamaria, Cirafici, Francesco, Merolla, Livia, Provitera, Roberto, Limongello, Nina, Dathan, Grieco, Domenico, Costanzo, Vincenzo, Fusco, Alfredo, Santoro, Massimo, and Carlomagno, Francesca more...
- Abstract
Introduction: The Nuclear Receptor Coactivator 4 (NCOA4) gene is frequently targeted by chromosomal rearrangements in thyroid carcinoma. These events join the 5’-ter of NCOA4 to the DNA sequence encoding the tyrosine kinase (TK) domain of the receptor tyrosine kinase RET, generating the RET/PTC3 chimeric gene, whose protein product displays oncogenic activity. The NCOA4 N-ter mediates homodimerization of the RET TK domain, followed by RET kinase activation and, in turn, gain of transforming activity. Matherials: We used Xenopus laevis egg extracts to study NCOA4 role in DNA replication by performing in vitro DNA replication assays, chromatin pull down and DNA fiber stretching; Mouse embryo fibroblasts (MEFs) from NCOA4+/+ and -/- embryos to study population doublings accumulation in culture, DNA damage and DNA damage response (DDR) activation by immufluorescence staining for γH2AX and 53BP1 and DNA fiber stretching to visualize replication stalling lesions, fork speed and inter-origin distance. Results: Here we show that NCOA4 protein binds MCM7 protein, a component of the MCM2-7 complex involved in DNA replication origin licensing and functioning as the major helicase of the DNA replication fork. In Xenopus laevis egg extracts, both exogenously expressed and endogenous NCOA4 protein inhibit DNA replication by interacting with the MCM2-7 complex and restraining replication origin activation, as shown by in vitro DNA replication assays, chromatin pull-down, and DNA fiber stretching experiments. NCOA4 -/- mouse embryonic fibroblasts (MEFs) undergo premature senescence, characterized by block of cell proliferation and SA-β galactosidase positive staining. This phenotype is characterized by replication stress-associated activation of DDR. Thus, using a DNA fiber stretching assay, we show that NCOA4 depleted cells accumulate replication stalling lesions and feature increased DNA replication origin activation. Conclusions: We conclude that NCOA4 protein is involved in the maintenance of genome integrity by controlling DNA replication , possibly acting as a new genome “caretaker”. Thus RET/PTC3 rearrangement in cancer may act as genetic double-hit by causing simultaneously a gain of oncogenic RET function and a loss of care-taker NCOA4 function. more...
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- 2012
12. Therapeutic strategies to target the receptor tyrosine kinase AXL in thyroid cancer
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GnanaPrakasam Krisnamoorthy, GUIDA, TERESA, VISCIANO, CARLA, LIOTTI, FEDERICA, CARLOMAGNO, Francesca, MELILLO, ROSA MARINA, European Thyroid Association, Gnanaprakasam, Krisnamoorthy, Guida, Teresa, Visciano, Carla, Liotti, Federica, Carlomagno, Francesca, and Melillo, ROSA MARINA more...
- Abstract
The AXL receptor tyrosine kinase is overexpressed and active in various cancer types including thyroid carcinoma, and several preclinical studies suggest that targeting AXL is an effective therapeutical strategy in AXL-positive cancers. Heat shock protein 90 (HSP90) acts as a molecular chaperone to regulate the conformation, activation, function and stability of many cancer-related kinases. Inhibition of HSP90 by geldanamycin and its derivative 17-Allyl-Ammino-17-demethoxygeldanamycin (17-AAG), leads to simultaneous combinatorial depletion of a wide range of HSP90 client proteins through the induction of their misfolding and proteasome-mediated degradation. The Quality control E3 ligase CHIP ubiquitinates misfolded proteins and favours their degradation. Here we show that treatment of AXL-expressing thyroid cancer cells with 17-AAG induces its proteasome-mediated degradation. Specifically, 17-AAG induces the down-regulation of the fully glycosilated, mature form of the receptor that is exposed on the plasmamembrane and responds to ligand stimulation. Degradation is preceded by AXL ubiquitination by CHIP. Endogenous and overexpressed AXL protein co-immunoprecipitated with CHIP and HSP90, and this complex is modified by 17-AAG treatment. By using different AXL mutants and AXL small molecule inhibitors, we demonstrate that AXL sensitivity to 17-AAG requires AXL kinase domain, but is not dependent on AXL kinase activity. Overall our data elucidate the biological basis of AXL downregulation by HSP 90 inhibition and suggest that Hsp90 inhibition could be effective in treating AXL expressing thyroid cancer. more...
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- 2012
13. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase
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Moccia, Marialuisa, primary, Liu, Qingsong, additional, Guida, Teresa, additional, Federico, Giorgia, additional, Brescia, Annalisa, additional, Zhao, Zheng, additional, Choi, Hwan Geun, additional, Deng, Xianming, additional, Tan, Li, additional, Wang, Jinhua, additional, Billaud, Marc, additional, Gray, Nathanael S., additional, Carlomagno, Francesca, additional, and Santoro, Massimo, additional more...
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- 2015
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14. A TECHNO-ECONOMIC ANALYSIS OF BIODIESEL PRODUCTION FROM MICROALGAE
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Olivieri, Giuseppe, primary, Guida, Teresa, additional, Salatino, Piero, additional, and Marzocchella, Antonio, additional
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- 2013
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15. Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474
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Carlomagno, Francesca, primary, Guida, Teresa, additional, Anaganti, Suresh, additional, Provitera, Livia, additional, Kjaer, Svend, additional, McDonald, Neil Q, additional, Ryan, Anderson J, additional, and Santoro, Massimo, additional more...
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- 2009
- Full Text
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16. Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor β Gatekeeper Mutants
- Author
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Guida, Teresa, primary, Anaganti, Suresh, additional, Provitera, Livia, additional, Gedrich, Richard, additional, Sullivan, Elizabeth, additional, Wilhelm, Scott M., additional, Santoro, Massimo, additional, and Carlomagno, Francesca, additional more...
- Published
- 2007
- Full Text
- View/download PDF
17. Molecular Mechanism of 17-Allylamino-17-demethoxygeldanamycin (17-AAG)-induced AXL Receptor Tyrosine Kinase Degradation
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Gnana P. Krishnamoorthy, Rosa Marina Melillo, Teresa Guida, Elvira Avilla, Luigi Alfano, Massimo Santoro, Francesca Carlomagno, Krishnamoorthy, GNAMA PRAKASAM, Guida, Teresa, Alfano, L, Avilla, Elvira, Santoro, Massimo, Carlomagno, Francesca, and Melillo, ROSA MARINA more...
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Glycosylation ,Leupeptins ,Lactams, Macrocyclic ,Ubiquitin-Protein Ligases ,Receptor Protein-Tyrosine Kinases ,Antineoplastic Agents ,macromolecular substances ,Biochemistry ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Catalytic Domain ,Proto-Oncogene Proteins ,Nitriles ,Benzoquinones ,polycyclic compounds ,Humans ,Protein Isoforms ,HSP90 Heat-Shock Proteins ,Protein Kinase Inhibitors ,Molecular Biology ,Aniline Compounds ,biology ,AXL receptor tyrosine kinase ,Protein Stability ,GAS6 ,Cell Membrane ,Ubiquitination ,tyrosine kinase ,Molecular Bases of Disease ,Cell Biology ,Geldanamycin ,targeted therapy ,Axl Receptor Tyrosine Kinase ,Hsp90 ,female genital diseases and pregnancy complications ,Ubiquitin ligase ,Protein Transport ,chemistry ,Proteolysis ,Quinolines ,biology.protein ,Cancer research ,Signal transduction ,Proteasome Inhibitors ,Receptor ,HeLa Cells ,Protein Binding ,Signal Transduction - Abstract
The receptor tyrosine kinase AXL is overexpressed in many cancer types including thyroid carcinomas and has well established roles in tumor formation and progression. Proper folding, maturation, and activity of several oncogenic receptor tyrosine kinases require HSP90 chaperoning. HSP90 inhibition by the antibiotic geldanamycin or its derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) causes destabilization of its client proteins. Here we show that AXL is a novel client protein of HSP90. 17-AAG induced a time- and dose-dependent down-regulation of endogenous or ectopically expressed AXL protein, thereby inhibiting AXL-mediated signaling and biological activity. 17-AAG-induced AXL down-regulation specifically affected fully glycosylated mature receptor present on cell membrane. By using biotin and [(35)S]methionine labeling, we showed that 17-AAG caused depletion of membrane-localized AXL by mediating its degradation in the intracellular compartment, thus restricting its exposure on the cell surface. 17-AAG induced AXL polyubiquitination and subsequent proteasomal degradation; under basal conditions, AXL co-immunoprecipitated with HSP90. Upon 17-AAG treatment, AXL associated with the co-chaperone HSP70 and the ubiquitin E3 ligase carboxyl terminus of HSC70-interacting protein (CHIP). Overexpression of CHIP, but not of the inactive mutant CHIP K30A, induced accumulation of AXL polyubiquitinated species upon 17-AAG treatment. The sensitivity of AXL to 17-AAG required its intracellular domain because an AXL intracellular domain-deleted mutant was insensitive to the compound. Active AXL and kinase-dead AXL were similarly sensitive to 17-AAG, implying that 17-AAG sensitivity does not require receptor phosphorylation. Overall our data elucidate the molecular basis of AXL down-regulation by HSP90 inhibitors and suggest that HSP90 inhibition in anticancer therapy can exert its effect through inhibition of multiple kinases including AXL. more...
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- 2013
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18. Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor β Gatekeeper Mutants
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Teresa Guida, Suresh Anaganti, Livia Provitera, Scott Wilhelm, Elizabeth H. Sullivan, Massimo Santoro, Richard W. Gedrich, Francesca Carlomagno, Guida, Teresa, Anaganti, S, Provitera, L, Gedrich, R, Sullivan, E, Wilhelm, Sm, Santoro, Massimo, and Carlomagno, Francesca more...
- Subjects
Niacinamide ,Sorafenib ,Cancer Research ,recettori tirosino chinasi ,Pyridines ,Antineoplastic Agents ,terapia bersaglio ,Biology ,Binding, Competitive ,Piperazines ,Cancro ,Inhibitory Concentration 50 ,Mice ,Adenosine Triphosphate ,Growth factor receptor ,medicine ,Animals ,Humans ,neoplasms ,Cell Proliferation ,Kinase ,Phenylurea Compounds ,Benzenesulfonates ,Autophosphorylation ,Imatinib ,Proto-Oncogene Proteins c-sis ,Proto-Oncogene Proteins c-kit ,Pyrimidines ,Imatinib mesylate ,Oncology ,Benzamides ,Mutation ,Imatinib Mesylate ,biology.protein ,Cancer research ,Interleukin-3 ,Tyrosine kinase ,Platelet-derived growth factor receptor ,medicine.drug - Abstract
Purpose: Targeting of KIT and platelet-derived growth factor receptor (PDGFR) tyrosine kinases by imatinib is an effective anticancer strategy. However, mutations of the gatekeeper residue (T670 in KIT and T681 in PDGFRβ) render the two kinases resistant to imatinib. The aim of this study was to evaluate whether sorafenib (BAY 43-9006), a multitargeted ATP-competitive inhibitor of KIT and PDGFR, was active against imatinib-resistant KIT and PDGFRβ kinases. Experimental Design: We used in vitro kinase assays and immunoblot with phosphospecific antibodies to determine the activity of sorafenib on KIT and PDGFRβ kinases. We also exploited reporter luciferase assays to measure the effects of sorafenib on KIT and PDGFRβ downstream signaling events. The activity of sorafenib on interleukin-3–independent proliferation of Ba/F3 cells expressing oncogenic KIT or its imatinib-resistant T670I mutant was also tested. Results: Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRβ (IC50 for KIT T670I, 60 nmol/L; IC50 for PDGFRβ T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC50 for KIT D816V, 3.8 μmol/L; IC50 for PDGFRβ D850V, 1.17 μmol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRβ gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation. Conclusions: Sorafenib might be a promising anticancer agent for patients carrying KIT and PDGFRβ gatekeeper mutations. more...
- Published
- 2007
- Full Text
- View/download PDF
19. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase
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Massimo Santoro, Jinhua Wang, Marc Billaud, Xianming Deng, Giorgia Federico, Hwan Geun Choi, Marialuisa Moccia, Francesca Carlomagno, Nathanael S. Gray, Qingsong Liu, Li Tan, Annalisa Brescia, Zheng Zhao, Teresa Guida, Moccia, Marialuisa, Liu, Qingsong, Guida, Teresa, Federico, Giorgia, Brescia, Annalisa, Zhao, Zheng, Choi, Hwan Geun, Deng, Xianming, Tan, Li, Wang, Jinhua, Billaud, Marc, Gray, Nathanael S, and Santoro, Massimo more...
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Niacinamide ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,Pyridines ,Mutant ,lcsh:Medicine ,Biology ,Transfection ,medicine.disease_cause ,Small Molecule Libraries ,ret ,tyrosine kinase inhibitors ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Phosphorylation ,lcsh:Science ,Protein Kinase Inhibitors ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Mutation ,Multidisciplinary ,Kinase ,Proto-Oncogene Proteins c-ret ,Autophosphorylation ,lcsh:R ,Molecular biology ,Protein Structure, Tertiary ,3. Good health ,Molecular Docking Simulation ,030220 oncology & carcinogenesis ,Benzamides ,NIH 3T3 Cells ,lcsh:Q ,Carcinogenesis ,Tyrosine kinase ,Protein Binding ,Research Article - Abstract
Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the ‘DFG-out’ inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the ‘gatekeeper’ V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET. more...
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- 2015
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20. BAY 43-9006 inhibition of oncogenic RET mutants
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Giancarlo Troncone, Scott Wilhelm, Giuliana Salvatore, Massimo Santoro, Suresh Anaganti, Francesca Carlomagno, Teresa Guida, Carlomagno, Francesca, Anaganti, S, Guida, Teresa, Salvatore, G, Troncone, Giancarlo, Wilhelm, Sm, and Santoro, Massimo more...
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Sorafenib ,Niacinamide ,Cancer Research ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,Pyridines ,Immunoblotting ,Transplantation, Heterologous ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Biology ,Transfection ,Drug Administration Schedule ,thyroid ,Inhibitory Concentration 50 ,Mice ,Internal medicine ,medicine ,Animals ,cancer ,Thyroid Neoplasms ,Kinase activity ,Tyrosine ,Enzyme Inhibitors ,Phosphorylation ,Thyroid cancer ,therapy ,Kinase ,Phenylurea Compounds ,Benzenesulfonates ,Cell Cycle ,Phosphotransferases ,Proto-Oncogene Proteins c-ret ,Fibroblasts ,medicine.disease ,Molecular biology ,Transplantation ,Endocrinology ,Oncology ,RET ,thyroid cancer ,Mutation ,NIH 3T3 Cells ,Tyrosine kinase ,medicine.drug - Abstract
Background : Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods : We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fi broblasts by using immunocomplex kinase assays and immunoblotting with phospho-specifi c antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fi broblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and fl ow cytometry. Growth of TT cell – derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results : BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC 50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fi broblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC 50 = 110 nM, 95% confi dence interval [CI] = 88 to 133 nM) or RET V804M (IC 50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts ( n = 7) was reduced from 72.5 to 44 mm 3 (difference = 28.5 mm 3 , 95% CI = 7 mm 3 to 50 mm 3 ), whereas in vehicle-treated mice ( n = 7), mean tumor volume increased to 408 mm 3 (difference = 320 mm 3 , 95% CI = 180 mm 3 to 460 mm 3 ; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions : BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study. [J Natl Cancer Inst 2006;98:326 – 34] more...
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- 2006
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21. Genetic alterations in differentiated thyroid cancer: what can be expected for gene expression profiling of thyroid carcinomas
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Santoro, M., Rosa Marina MELILLO, Carlomagno, F., Castellone, M. D., Vitagliano, D., Guida, T., Vecchio, G., Fusco, A., Santoro, Massimo, Melillo, ROSA MARINA, Carlomagno, Francesca, Castellone, MARIA DOMENICA, Vitagliano, Donata, Guida, Teresa, Vecchio, Giancarlo, and Fusco, Alfredo more...
- Subjects
Oncogene Proteins ,Gene Expression Profiling ,Mutation ,Proto-Oncogene Proteins c-ret ,Animals ,Humans ,Receptor Protein-Tyrosine Kinases ,Thyroid Neoplasms ,Receptor, trkA ,Carcinoma, Papillary - Published
- 2003
22. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases
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Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Aj, Ryan, Gabriella Fontanini, Fusco A, Santoro M, Carlomagno, Francesca, Vitagliano, Donata, Guida, Teresa, Ciardiello, Fortunato, Tortora, Giampaolo, Vecchio, Giancarlo, Ryan, A. J., Fontanini, G., Fusco, Alfredo, Santoro, Massimo, Carlomagno, F, Vitagliano, D, Guida, T, Tortora, G, Vecchio, G, Ryan, Aj, Fontanini, G, Fusco, A, and Santoro, M. more...
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,Mice, Nude ,ZD6474 ,Mice ,Piperidines ,KDR ,Proto-Oncogene Proteins ,Animals ,Drosophila Proteins ,TKI ,RET ,Thyroid Neoplasms ,Enzyme Inhibitors ,Phosphorylation ,neoplasms ,Mice, Inbred BALB C ,Proto-Oncogene Proteins c-ret ,Receptor Protein-Tyrosine Kinases ,3T3 Cells ,Vascular Endothelial Growth Factor Receptor-2 ,Carcinoma, Papillary ,Cell Transformation, Neoplastic ,Quinazolines ,Signal Transduction - Abstract
RET/papillary thyroid carcinoma (PTC) oncogenes, generated by recombination of the tyrosine kinase-encoding domain of RET with different heterologous genes, are prevalent in papillary carcinomas of the thyroid. Point mutations of RET cause multiple endocrine neoplasia type 2 (MEN2) familial cancer syndrome and are found in sporadic medullary thyroid carcinomas. Here, we show that ZD6474, a low molecular weight tyrosine kinase inhibitor, blocks the enzymatic activity of RET-derived oncoproteins at a one-half maximal inhibitory concentration of 100 nM. ZD6474 blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an epidermal growth factor (EGF)-activated EGF-receptor/RET chimeric receptor. RET/PTC3-transformed cells-treated ZD6474 lost proliferative autonomy and showed morphological reversion. ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements. Finally, it blocked anchorage-independent growth of RET/PTC3-transformed NIH3T3 fibroblasts and the formation of tumors after injection of NIH-RET/PTC3 cells into nude mice. Thus, targeting RET oncogenes with ZD6474 might offer a potential treatment strategy for carcinomas sustaining oncogenic activation of RET. more...
- Published
- 2002
23. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes
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Carlomagno, F., Vitagliano, D., Guida, T., Napolitano, M., Vecchio, G., Alfredo Fusco, Gazit, A., Levitzki, A., Santoro, M., Carlomagno, Francesca, Vitagliano, Donata, Guida, Teresa, Napolitano, M., Vecchio, Giancarlo, Fusco, Alfredo, Gazit, A., Levitzki, A., and Santoro, Massimo more...
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,kinase ,Gene Expression ,macromolecular substances ,thyroid ,Gonadotropin-Releasing Hormone ,Mice ,Proto-Oncogene Proteins ,Tumor Cells, Cultured ,Animals ,Drosophila Proteins ,Humans ,Thyroid Neoplasms ,Enzyme Inhibitors ,Phosphorylation ,ret ,neoplasms ,Mice, Inbred BALB C ,Proto-Oncogene Proteins c-ret ,Receptor Protein-Tyrosine Kinases ,3T3 Cells ,Oncogenes ,Cell Transformation, Neoplastic ,Pyrimidines ,Pyrazoles ,Signal Transduction - Abstract
Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 microM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms. more...
- Published
- 2002
24. Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants.
- Author
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Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, and Carlomagno F
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- Adenosine Triphosphate metabolism, Animals, Antineoplastic Agents pharmacology, Benzamides, Binding, Competitive, Cell Proliferation, Humans, Imatinib Mesylate, Inhibitory Concentration 50, Interleukin-3 metabolism, Mice, Niacinamide analogs & derivatives, Phenylurea Compounds, Sorafenib, Benzenesulfonates pharmacology, Mutation, Piperazines pharmacology, Proto-Oncogene Proteins c-kit metabolism, Proto-Oncogene Proteins c-sis genetics, Proto-Oncogene Proteins c-sis metabolism, Pyridines pharmacology, Pyrimidines pharmacology
- Abstract
Purpose: Targeting of KIT and platelet-derived growth factor receptor (PDGFR) tyrosine kinases by imatinib is an effective anticancer strategy. However, mutations of the gatekeeper residue (T670 in KIT and T681 in PDGFRbeta) render the two kinases resistant to imatinib. The aim of this study was to evaluate whether sorafenib (BAY 43-9006), a multitargeted ATP-competitive inhibitor of KIT and PDGFR, was active against imatinib-resistant KIT and PDGFRbeta kinases., Experimental Design: We used in vitro kinase assays and immunoblot with phosphospecific antibodies to determine the activity of sorafenib on KIT and PDGFRbeta kinases. We also exploited reporter luciferase assays to measure the effects of sorafenib on KIT and PDGFRbeta downstream signaling events. The activity of sorafenib on interleukin-3-independent proliferation of Ba/F3 cells expressing oncogenic KIT or its imatinib-resistant T670I mutant was also tested., Results: Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRbeta (IC(50) for KIT T670I, 60 nmol/L; IC(50) for PDGFRbeta T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC(50) for KIT D816V, 3.8 micromol/L; IC(50) for PDGFRbeta D850V, 1.17 micromol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRbeta gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation., Conclusions: Sorafenib might be a promising anticancer agent for patients carrying KIT and PDGFRbeta gatekeeper mutations. more...
- Published
- 2007
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25. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
- Author
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Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, and Brunetti C more...
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Camptothecin administration & dosage, Camptothecin analogs & derivatives, Colorectal Neoplasms pathology, Disease Progression, Female, Fluorouracil administration & dosage, Humans, Infusions, Intravenous, Leucovorin administration & dosage, Male, Middle Aged, Organoplatinum Compounds administration & dosage, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms drug therapy
- Abstract
Purpose: We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer., Patients and Methods: A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m(2) on day 1 with LV 100 mg/m(2) administered as a 2-hour infusion before FU 400 mg/m(2) administered as an intravenous bolus injection, and FU 600 mg/m(2) as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m(2) on day 1 with LV5FU2 regimen)., Results: One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed., Conclusion: There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile. more...
- Published
- 2005
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26. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes.
- Author
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Carlomagno F, Vitagliano D, Guida T, Napolitano M, Vecchio G, Fusco A, Gazit A, Levitzki A, and Santoro M
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- 3T3 Cells cytology, 3T3 Cells drug effects, Animals, Cell Transformation, Neoplastic metabolism, Gene Expression, Humans, Male, Mice, Mice, Inbred BALB C, Oncogenes, Phosphorylation drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction drug effects, Signal Transduction physiology, Thyroid Neoplasms drug therapy, Thyroid Neoplasms enzymology, Thyroid Neoplasms genetics, Tumor Cells, Cultured, Cell Transformation, Neoplastic drug effects, Drosophila Proteins, Enzyme Inhibitors pharmacology, Gonadotropin-Releasing Hormone analogs & derivatives, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, Pyrazoles pharmacology, Pyrimidines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics
- Abstract
Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 microM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms. more...
- Published
- 2002
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