5 results on '"Mangano, Raffaella"'
Search Results
2. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.
- Author
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Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, and Plummer R
- Subjects
- Adult, Aged, Breast Neoplasms genetics, Breast Neoplasms pathology, Cohort Studies, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Heterozygote, Humans, Indoles pharmacokinetics, Middle Aged, Neoplasm Staging, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Prognosis, Tissue Distribution, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms drug therapy, Germ-Line Mutation genetics, Indoles therapeutic use, Ovarian Neoplasms drug therapy
- Abstract
Background: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers., Methods: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0-1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles., Results: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84-567 days)., Conclusions: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose-response has its limitations.
- Published
- 2016
- Full Text
- View/download PDF
3. A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation.
- Author
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Bergamini G, Bell K, Shimamura S, Werner T, Cansfield A, Müller K, Perrin J, Rau C, Ellard K, Hopf C, Doce C, Leggate D, Mangano R, Mathieson T, O'Mahony A, Plavec I, Rharbaoui F, Reinhard F, Savitski MM, Ramsden N, Hirsch E, Drewes G, Rausch O, Bantscheff M, and Neubauer G
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Arthritis, Experimental drug therapy, Arthritis, Experimental immunology, Arthritis, Experimental pathology, Binding, Competitive, Cell Line, Cell Movement drug effects, Class Ib Phosphatidylinositol 3-Kinase, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Molecular Structure, Rats, Rats, Wistar, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacokinetics, Small Molecule Libraries therapeutic use, Structure-Activity Relationship, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer enzymology, T-Lymphocytes, Helper-Inducer immunology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cell Differentiation drug effects, Enzyme Inhibitors pharmacology, Interleukin-17 immunology, Phosphoinositide-3 Kinase Inhibitors, Small Molecule Libraries pharmacology, T-Lymphocytes, Helper-Inducer drug effects
- Abstract
We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.
- Published
- 2012
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4. Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists.
- Author
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Cramp S, Dyke HJ, Higgs C, Clark DE, Gill M, Savy P, Jennings N, Price S, Lockey PM, Norman D, Porres S, Wilson F, Jones A, Ramsden N, Mangano R, Leggate D, Andersson M, and Hale R
- Subjects
- Animals, Biological Availability, Drug Discovery, Histamine Antagonists chemistry, Histamine Antagonists pharmacokinetics, Inhibitory Concentration 50, Macaca fascicularis, Rats, Receptors, Histamine, Receptors, Histamine H4, Stereoisomerism, Histamine Antagonists pharmacology, Receptors, G-Protein-Coupled antagonists & inhibitors
- Abstract
The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H(4) receptor inverse agonists is described. The initial hit, 3A (IC(50) 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC(50) 1 nM) as well as enhanced microsomal stability., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
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5. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
- Author
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Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, and Superti-Furga G
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Chaperonins, Chromatography, Affinity methods, Enzyme Activation, HSP90 Heat-Shock Proteins genetics, HSP90 Heat-Shock Proteins metabolism, Humans, I-kappa B Proteins isolation & purification, I-kappa B Proteins metabolism, MAP Kinase Kinase Kinase 3, MAP Kinase Kinase Kinases genetics, MAP Kinase Kinase Kinases metabolism, Macromolecular Substances, Mass Spectrometry methods, Models, Biological, Molecular Chaperones genetics, Molecular Chaperones metabolism, NF-kappa B genetics, NF-kappa B isolation & purification, Proteome analysis, RNA Interference, Receptors, Tumor Necrosis Factor metabolism, Tacrolimus Binding Proteins genetics, Tacrolimus Binding Proteins metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha isolation & purification, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Drosophila Proteins, NF-kappa B metabolism, Signal Transduction physiology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.
- Published
- 2004
- Full Text
- View/download PDF
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