44 results on '"ALTOMARE, EMANUELA"'
Search Results
2. miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma
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Rossi, Marco, Altomare, Emanuela, Botta, Cirino, Gallo Cantafio, Maria Eugenia, Sarvide, Sarai, Caracciolo, Daniele, Riillo, Caterina, Gaspari, Marco, Taverna, Domenico, Conforti, Francesco, Critelli, Paola, Bertucci, Bernardo, Iannone, Michelangelo, Polerà, Nicoletta, Scumaci, Domenica, Arbitrio, Mariamena, Amodio, Nicola, Di Martino, Maria Teresa, Paiva, Bruno, Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
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- 2021
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3. Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis
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Arbitrio, Mariamena, Di Martino, Maria Teresa, Barbieri, Vito, Agapito, Giuseppe, Guzzi, Pietro Hiram, Botta, Cirino, Iuliano, Eleonora, Scionti, Francesca, Altomare, Emanuela, Codispoti, Stefania, Conforti, Serafino, Cannataro, Mario, Tassone, Pierfrancesco, and Tagliaferri, Pierosandro
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- 2016
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4. TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma
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Scionti, Francesca, primary, Juli, Giada, additional, Rocca, Roberta, additional, Caracciolo, Daniele, additional, Riillo, Caterina, additional, Polerà, Nicoletta, additional, Grillone, Katia, additional, Altomare, Emanuela, additional, Caparello, Basilio, additional, Arbitrio, Mariamena, additional, Alcaro, Stefano, additional, Tagliaferri, Pierosandro, additional, Tassone, Pierfrancesco, additional, and Martino, Maria Teresa Di, additional
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- 2022
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5. Translational aspects of the modern genetics in head and neck cancers
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PADUANO, FRANCESCO, primary, ALTOMARE, EMANUELA, additional, MARRELLI, BENEDETTA, additional, DATTILO, VINCENZO, additional, MOHD HUSSAINI, HAIZAL, additional, ROY COOPER, PAUL, additional, and TATULLO, MARCO, additional
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- 2022
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6. Synthetic isoforms of endogenous sulfatides differently modulate indoleamine 2,3-dioxygenase in antigen presenting cells
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Altomare, Emanuela, Fallarini, Silvia, Battaglini, Carolina Orsi, Mossotti, Matteo, Panza, Luigi, and Lombardi, Grazia
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- 2011
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7. Translational aspects of themodern genetics in head and neck cancers.
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PADUANO, FRANCESCO, ALTOMARE, EMANUELA, MARRELLI, BENEDETTA, DATTILO, VINCENZO, HUSSAINI, HAIZAL MOHD, COOPER, PAUL ROY, and TATULLO, MARCO
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TREATMENT of oral cancer , *SCIENTIFIC community , *SCIENTIFIC literature - Abstract
Oral cancer (OC) is one of the most recurrent cancers in the head and neck squamous cancer (SCCHN) category. Recently, the genome-wide association studies (GWAS) have gained growing interest in the scientific community. GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN. This systematic overview aims to critically evaluate the latest data reported within the scientific literature. The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis, involving other clinical and systemic co-factors. PubMed, Google Scholar, and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years, reporting studies on the main queries addressed in this work. This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers, clarifying and updating the role of genetic factors in SCCHN onset and development. The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Polymorphic Variants in NR1I3 and UGT2B7 Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case-Control Study
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Arbitrio, Mariamena, Scionti, Francesca, Altomare, Emanuela, Di Martino, Maria Teresa, Agapito, Giuseppe, Galeano, Teresa, Staropoli, Nicoletta, Iuliano, Eleonora, Grillone, Francesco, Fabiani, Fernanda, Caracciolo, Daniele, Cannataro, Mario, Arpino, Grazia, Santini, Daniele, Tassone, Pierfrancesco, Tagliaferri, Pierosandro, Arbitrio, Mariamena, Scionti, Francesca, Altomare, Emanuela, Di Martino, Maria Teresa, Agapito, Giuseppe, Galeano, Teresa, Staropoli, Nicoletta, Iuliano, Eleonora, Grillone, Francesco, Fabiani, Fernanda, Caracciolo, Daniele, Cannataro, Mario, Arpino, Grazia, Santini, Daniele, Tassone, Pierfrancesco, and Tagliaferri, Pierosandro
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Paclitaxel ,Prognosi ,Receptors, Cytoplasmic and Nuclear ,Peripheral Nervous System Diseases ,Docetaxel ,Middle Aged ,Polymorphism, Single Nucleotide ,Biomarkers, Pharmacological ,Pharmacogenomic Testing ,Antineoplastic Agent ,Outcome Assessment, Health Care ,Female ,Glucuronosyltransferase ,Case-Control Studie ,Constitutive Androstane Receptor ,Breast Neoplasm ,Human - Abstract
Taxane-related peripheral neuropathy (TrPN) is a dose-limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug-metabolizing enzyme and transporter microarray platform, in a retrospective case-control study, the correlation between ADME polymorphic variants and grades≥2-3-TrPN was investigated. In a breast cancer (BC) training set, five single-nucleotide polymorphisms in NR1I3 and UDP-glucuronosyltransferase (UGT)2B7 genes were correlated to grades≥2-3-TrPN protection. By receiver operating characteristic curves, the grades≥2-3-TrPN-related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel-TrPN and UGT2B7 to docetaxel-TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants.
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- 2019
9. Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia
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Caracciolo, Daniele, primary, Riillo, Caterina, additional, Ballerini, Andrea, additional, Gaipa, Giuseppe, additional, Lhermitte, Ludovic, additional, Rossi, Marco, additional, Botta, Cirino, additional, Duroyon, Eugénie, additional, Grillone, Katia, additional, Gallo Cantafio, Maria Eugenia, additional, Buracchi, Chiara, additional, Alampi, Greta, additional, Gulino, Alessandro, additional, Belmonte, Beatrice, additional, Conforti, Francesco, additional, Golino, Gaetanina, additional, Juli, Giada, additional, Altomare, Emanuela, additional, Polerà, Nicoletta, additional, Scionti, Francesca, additional, Arbitrio, Mariamena, additional, Iannone, Michelangelo, additional, Martino, Massimo, additional, Correale, Pierpaolo, additional, Talarico, Gabriella, additional, Ghelli Luserna di Rorà, Andrea, additional, Ferrari, Anna, additional, Concolino, Daniela, additional, Sestito, Simona, additional, Pensabene, Licia, additional, Giordano, Antonio, additional, Hildinger, Markus, additional, Di Martino, Maria Teresa, additional, Martinelli, Giovanni, additional, Tripodo, Claudio, additional, Asnafi, Vahid, additional, Biondi, Andrea, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2021
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10. DMET(TM) Genotyping: Tools for Biomarkers Discovery in the Era of Precision Medicine
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Agapito Giuseppe, Settino Marzia, Scionti Francesca, Altomare Emanuela, Guzzi Pietro Hiram, Tassone Pierfrancesco, Tagliaferri Pierosandro, Cannataro Mario, Arbitrio Mariamena, and Di Martino Maria Teresa
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ComputingMethodologies_PATTERNRECOGNITION ,DMETTM platform ,GMQL ,SNPs ,bioinformatic tools ,pharmacogenomics - Abstract
The knowledge of genetic variants in genes involved in drug metabolism may be translated into reduction of adverse drug reactions, increase of efficacy, healthcare outcomes improvement and economic benefits. Many high-throughput tools are available for the genotyping of Single Nucleotide Polymorphisms (SNPs) known to be related to drugs and xenobiotics metabolism. DMETTM platform represents an example of SNPs panel to discover biomarkers correlated to efficacy or toxicity in common and rare diseases. The difficulty in analyzing the mole of information generated by DMETTM platform led to the development and implementation of algorithms and tools for statistical and data mining analysis. These softwares allow efficient handling of the omics data to validate the explorative SNPs identified by DMET assay and to correlate them with drug efficacy, toxicity and/or cancer susceptibility. In this review we present a suite of bioinformatic frameworks for the preprocessing and analysis of DMET-SNPs data. In particular, we introduce a workflow that uses the GenoMetric Query Language, a high-level query language specifically designed for genomics, able to query public datasets (such as ENCODE, TCGA, GENCODE annotation dataset, etc.) as well as to combine them with private datasets (e.g., output from Affymetrix® DMETTM Platform).
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- 2020
11. miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma
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Rossi, Marco, primary, Altomare, Emanuela, additional, Botta, Cirino, additional, Gallo Cantafio, Maria Eugenia, additional, Sarvide, Sarai, additional, Caracciolo, Daniele, additional, Riillo, Caterina, additional, Gaspari, Marco, additional, Taverna, Domenico, additional, Conforti, Francesco, additional, Critelli, Paola, additional, Bertucci, Bernardo, additional, Iannone, Michelangelo, additional, Polerà, Nicoletta, additional, Scumaci, Domenica, additional, Arbitrio, Mariamena, additional, Amodio, Nicola, additional, Di Martino, Maria Teresa, additional, Paiva, Bruno, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
- Published
- 2020
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12. DMETTM Genotyping: Tools for Biomarkers Discovery in the Era of Precision Medicine
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Agapito, Giuseppe, primary, Settino, Marzia, additional, Scionti, Francesca, additional, Altomare, Emanuela, additional, Guzzi, Pietro Hiram, additional, Tassone, Pierfrancesco, additional, Tagliaferri, Pierosandro, additional, Cannataro, Mario, additional, Arbitrio, Mariamena, additional, and Di Martino, Maria Teresa, additional
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- 2020
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13. Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma
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Caracciolo, Daniele, primary, Scionti, Francesca, additional, Juli, Giada, additional, Altomare, Emanuela, additional, Golino, Gaetanina, additional, Todoerti, Katia, additional, Grillone, Katia, additional, Riillo, Caterina, additional, Arbitrio, Mariamena, additional, Iannone, Michelangelo, additional, Morelli, Eugenio, additional, Amodio, Nicola, additional, Di Martino, Maria Teresa, additional, Rossi, Marco, additional, Neri, Antonino, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2020
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14. Global Rnaseq/Proteomic-Phoshoproteomic Analysis Unveil Mir-21 As a Central Player in Driving Th17 Mediated Bone Disease in MM
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Rossi, Marco, primary, Altomare, Emanuela, primary, Botta, Cirino, primary, Gallo Cantafio, Maria Eugenia, primary, Gaspari, Marco, primary, Taverna, Domenico, primary, Sarai, Sarvide, primary, Caracciolo, Daniele, primary, Critelli, Paola, primary, Conforti, Francesco, primary, Di Martino, Maria Teresa, primary, Paiva, Bruno, primary, Tagliaferri, Pierosandro, primary, and Tassone, Pierfrancesco, primary
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- 2019
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15. PARP1-Mediated Alt-NHEJ Repair Is a Therapeutic Target in Multiple Myeloma
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Caracciolo, Daniele, primary, Juli, Giada, additional, Scionti, Francesca, additional, Golino, Gaetanina, additional, Arbitrio, Mariamena, additional, Altomare, Emanuela, additional, Todoerti, Katia, additional, Grillone, Katia, additional, Di Martino, Maria Teresa, additional, Rossi, Marco, additional, Neri, Antonino, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
- Published
- 2019
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16. Polymorphic variants in NR1I3 and UGT2B7 predict taxane neurotoxicity and have prognostic relevance in breast cancer patients: a case-control study
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Arbitrio Mariamena (1), Scionti Francesca (2), Altomare Emanuela (2), Di Martino Maria Teresa (2), Agapito Giuseppe (3), Galeano Teresa (2), Staropoli Nicoletta (4), Iuliano Eleonora(2), Grillone rancescaF (4), Fabiani Fernanda (5), Caracciolo Daniele (2), Cannataro Mario (3), Arpino Grazia (6), Santini Daniele (7), Tassone Pierfrancesco (2, and Tagliaferri Pierosandro (2
- Subjects
DMET ,ADME genes ,Neurotoxicity ,Single Nucleotide Polymorphism ,Taxane ,genomic signature - Abstract
Taxane-related peripheral neuropathy (TrPN) is a dose-limiting toxicity with important inter-individual variability. Genetic polymorphisms in ADME genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix DMETTM microarray platform, in a retrospective case-control study, the correlation between ADME polymorphic variants and grade >=2-3 TrPN (G>=2-3 TrPN) was investigated. In a breast cancer (BC) training set, 5 SNPs in NR1I3 and UGT2B7genes were correlated to G>=2-3-TrPN protection. By ROC curves, the G>=2-3-TrPN-related candidate biomarkers in an independent series of 54 BC patients (17 cases and 37 controls) were validated. NR1I3 was correlated to Paclitaxel-TrPN and UGT2B7 to Docetaxel-TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of BC patients for prevention of treatment failure in ultrametabolizer genetic variants.
- Published
- 2019
17. Inhibition of miR-21 as an innovative approach, to target Bone Disease, related to Th17 cells in Multiple Myeloma
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Altomare Emanuela, Rossi Marco, Botta Cirino, Gallo Cantafio Maria Eugenia, Gaspari Marco, Taverna D, Sarvide Sarai, Caracciolo Daniele, Critelli P, Conforti Francesco, Amodio Nicola, Arbitrio Mariamena, Di Martino Maria Teresa, Paiva Bruno, San Miguel J, Tagliaferri Pierosandro, and Tassone Pierfrancesco
- Subjects
NA - Abstract
Multiple myeloma (MM) is a malignant plasma cell disease that accounts for approximately 10% of all hematologic cancers, dependent on inflammatory bone marrow microenvironment (BMM). Bone disease (BD) is a hallmark of MM and is characterized by severe skeleton damage, reduced quality of life and overall survival. Interleukin (IL)-17 producing CD4+ T cells (Th17) trigger MM cells growth and osteclast-dependent bone damage. In turn, Th17 generation and function rely on inflammatory stimuli. There is compelling evidence that miR-21 is a central player in Th17 effector functions. Our preliminary data have shown that miR-21 is highly upregulated in MM-Th17 isolated from patients with active BD as compared to MM with no active BD and controls. So, we investigated the role of miR-21, which is an inflammation induced miRNA, in Th17-mediated MM tumor growth and bone disease. Indeed, we have been able to negatively modulate Th17 differentiation by a specific inhibitor of miR-21 (mir21i). The overall effect of mir-21 inhibition is the suppression of OCL resorptive activity, thus attenuating Th17 mediated multiple myeloma bone disease (MMBD). We found that Inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired differentiation towards Th17 in vitro. Analysis of miR-21-related molecular pathways in Th17 cells demonstrated upregulation of STAT-1/-5a-5b, downregulation of STAT-3 and redirection of Th17 to Th1/activated like cells as shown by a pair-to-pair RNAseq and proteome/phosphoproteome analysis. Inhibition of Th17 by miR-21 impaired MM cell proliferation and osteoclast activity in vitro. We recapitulated and validated these findings in NOD/SCID gNULL mice, injected intratibially with miR-21i-T cells and MM cells. Our findings disclose the critical involvement of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract BMM-dependent MM development and related BD.
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- 2019
18. Polymorphic Variants inNR 1I3andUGT 2B7Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case‐Control Study
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Arbitrio, Mariamena, primary, Scionti, Francesca, additional, Altomare, Emanuela, additional, Di Martino, Maria Teresa, additional, Agapito, Giuseppe, additional, Galeano, Teresa, additional, Staropoli, Nicoletta, additional, Iuliano, Eleonora, additional, Grillone, Francesco, additional, Fabiani, Fernanda, additional, Caracciolo, Daniele, additional, Cannataro, Mario, additional, Arpino, Grazia, additional, Santini, Daniele, additional, Tassone, Pierfrancesco, additional, and Tagliaferri, Pierosandro, additional
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- 2019
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19. Activation of the Non-Canonical Estrogen Receptor Gper As a Novel Therapeutic Strategy Against Waldenström Macroglobulinemia
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Amodio, Nicola, primary, Juli, Giada, additional, Morelli, Eugenio, additional, Stamato, Maria Angelica, additional, Gallo Cantafio, Maria Eugenia, additional, Federico, Cinzia, additional, Todoerti, Katia, additional, Altomare, Emanuela, additional, Grillone, Katia, additional, Rossi, Marco, additional, Cea, Michele, additional, Neri, Antonino, additional, Fulciniti, Mariateresa, additional, Munshi, Nikhil, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
- Published
- 2018
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20. The potential role of miRNAs in multiple myeloma therapy
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Caracciolo, Daniele, primary, Montesano, Martina, additional, Altomare, Emanuela, additional, Scionti, Francesca, additional, Di Martino, Maria Teresa, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
- Published
- 2018
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21. miR-22 suppresses DNA ligase III addiction in multiple myeloma
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Caracciolo, Daniele, primary, Di Martino, Maria Teresa, additional, Amodio, Nicola, additional, Morelli, Eugenio, additional, Montesano, Martina, additional, Botta, Cirino, additional, Scionti, Francesca, additional, Talarico, Daniela, additional, Altomare, Emanuela, additional, Gallo Cantafio, Maria Eugenia, additional, Zuccalà, Valeria, additional, Maltese, Lorenza, additional, Todoerti, Katia, additional, Rossi, Marco, additional, Arbitrio, Mariamena, additional, Neri, Antonino, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
- Published
- 2018
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22. Abstract 1783: UMG1, a novel humanized monoclonal antibody against a glysosylated-CD43-related epitope, induces antibody-dependent cellular cytotoxicity (ADCC) on human T-cell acute lymphoblastic leukemia cells
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Botta, Cirino, primary, Cantafio, Maria E. Gallo, additional, Buracchi, Chiara, additional, Siciliano, Maria A., additional, Cucè, Maria, additional, Riillo, Caterina, additional, Tuccillo, Franca M., additional, Caracciolo, Daniele, additional, Altomare, Emanuela, additional, Arbitrio, Mariamena, additional, Martino, Maria T. Di, additional, Rossi, Marco, additional, Biondi, Andrea, additional, Gaipa, Giuseppe, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2018
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23. Abstract 2827: Alternative non-homologous end joining DNA repair as therapeutic target in multiple myeloma
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Caracciolo, Daniele, primary, Montesano, Martina, additional, Altomare, Emanuela, additional, Consolo, Grazia, additional, Amodio, Nicola, additional, Martino, Maria Teresa Di, additional, Rossi, Marco, additional, Botta, Cirino, additional, Morelli, Eugenio, additional, Juli, Giada, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2018
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24. Abstract 4431: Phosphoproteomic analysis of miR-21 modulation in Th17 cells: Potential implications for multiple myeloma bone disease therapy
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Altomare, Emanuela, primary, Rossi, Marco, additional, Caracciolo, Daniele, additional, Amodio, Nicola, additional, Gaspari, Marco, additional, Taverna, Domenico, additional, Scumaci, Domenica, additional, Botta, Cirino, additional, Gullà, Annamaria, additional, Morelli, Eugenio, additional, Critelli, Paola, additional, Arbitrio, Mariamena, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2018
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25. Abstract 2550: Anti-MALAT1 synthetic oligonucleotides target the proteasome and exert anti-multiple myeloma activity
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Stamato, Maria Angelica, primary, Amodio, Nicola, additional, Morelli, Eugenio, additional, Juli, Giada, additional, Manzoni, Martina, additional, Cantafio, Maria Eugenia Gallo, additional, Biamonte, Lavinia, additional, Taiana, Elisa, additional, Gullà, Annamaria, additional, Altomare, Emanuela, additional, Scionti, Francesca, additional, Caracciolo, Daniele, additional, Botta, Cirino, additional, Cucè, Maria, additional, Arbitrio, Mariamena, additional, Martino, Maria Teresa Di, additional, Rossi, Marco, additional, Neri, Antonino, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2017
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26. Abstract 1066: Synthetic miR-22 inhibits alternative non homologous end-joining DNA repair and increases sensitivity to PARP-inhibition in multiple myeloma cells
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Caracciolo, Daniele, primary, Morelli, Eugenio, additional, Di Martino, Maria Teresa, additional, Talarico, Daniela, additional, Botta, Cirino, additional, Amodio, Nicola, additional, Federico, Cinzia, additional, Altomare, Emanuela, additional, Biamonte, Lavinia, additional, Stamato, Maria Angelica, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2016
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27. Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis
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Arbitrio, Mariamena, primary, Di Martino, Maria Teresa, additional, Barbieri, Vito, additional, Agapito, Giuseppe, additional, Guzzi, Pietro Hiram, additional, Botta, Cirino, additional, Iuliano, Eleonora, additional, Scionti, Francesca, additional, Altomare, Emanuela, additional, Codispoti, Stefania, additional, Conforti, Serafino, additional, Cannataro, Mario, additional, Tassone, Pierfrancesco, additional, and Tagliaferri, Pierosandro, additional
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- 2015
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28. miR-22 suppresses DNA ligase III addiction in multiple myeloma
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Caracciolo, Daniele, Di Martino, Maria, Amodio, Nicola, Morelli, Eugenio, Montesano, Martina, Botta, Cirino, Scionti, Francesca, Talarico, Daniela, Altomare, Emanuela, Gallo Cantafio, Maria, Zuccalà, Valeria, Maltese, Lorenza, Todoerti, Katia, Rossi, Marco, Arbitrio, Mariamena, Neri, Antonino, Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
- Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.
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- 2019
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29. Abstract 4789: In vitro and vivo activity against multiple myeloma cells of a novel locked nucleic acid (LNA)-miR-221 inhibitor
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Martino, Maria Teresa Di, primary, Cantafio, Maria Eugenia Gallo, additional, Gullà, Annamaria, additional, Altomare, Emanuela, additional, Morelli, Eugenio, additional, Amodio, Nicola, additional, Leone, Emanuela, additional, Botta, Cirino, additional, Frandsen, Niels M., additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2014
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30. Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro
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Marvaso, Giulia, primary, Barone, Agnese, additional, Amodio, Nicola, additional, Raimondi, Lavinia, additional, Agosti, Valter, additional, Altomare, Emanuela, additional, Scotti, Valerio, additional, Lombardi, Angela, additional, Bianco, Roberto, additional, Bianco, Cataldo, additional, Caraglia, Michele, additional, Tassone, Pierfrancesco, additional, and Tagliaferri, Pierosandro, additional
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- 2014
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31. Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity
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Raimondi, Lavinia, primary, Amodio, Nicola, additional, Di Martino, Maria Teresa, additional, Altomare, Emanuela, additional, Leotta, Marzia, additional, Caracciolo, Daniele, additional, Gullà, Annamaria, additional, Neri, Antonino, additional, Taverna, Simona, additional, D’Aquila, Patrizia, additional, Alessandro, Riccardo, additional, Giordano, Antonio, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2014
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32. In Vitro and In Vivo Activity of a Novel Locked Nucleic Acid (LNA)-Inhibitor-miR-221 against Multiple Myeloma Cells
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Di Martino, Maria Teresa, primary, Gullà, Annamaria, additional, Gallo Cantafio, Maria Eugenia, additional, Altomare, Emanuela, additional, Amodio, Nicola, additional, Leone, Emanuela, additional, Morelli, Eugenio, additional, Lio, Santo Giovanni, additional, Caracciolo, Daniele, additional, Rossi, Marco, additional, Frandsen, Niels M., additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2014
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33. Synthetic MiR-29b Mimics Potentiate Dendritic-Cell Based Immunotherapy Against Multiple Myeloma In Vitro and In Vivo
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Botta, Cirino, primary, Rossi, Marco, additional, Pitari, Maria Rita, additional, Gullà, Annamaria, additional, Del Giudice, Teresa, additional, Morelli, Eugenio, additional, Iuliano, Eleonora, additional, Altomare, Emanuela, additional, Amodio, Nicola, additional, Di Martino, Maria Teresa, additional, Correale, Pierpaolo, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2013
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34. In Vitro and Vivo Activity Against Multiple Myeloma Cells Of a Novel Locked Nucleic Acid (LNA)-Mir-221 Inhibitor
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Di Martino, Maria Teresa, primary, Gullà, Annamaria, additional, Gallo Cantafio, Maria Eugenia, additional, Altomare, Emanuela, additional, Amodio, Nicola, additional, Leone, Emanuela, additional, Lio, Santo Giovanni, additional, Morelli, Eugenio, additional, Caracciolo, Daniele, additional, Botta, Cirino, additional, Neri, Antonino, additional, Frandsen, Niels M, additional, Tagliaferri, Pierosandro, additional, and Tassone, Pierfrancesco, additional
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- 2013
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35. Increased frequency of circulating invariant natural killer T cells in malignant pleural mesothelioma patients
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Altomare, Emanuela, primary, Fallarini, Silvia, additional, Biaggi, Gabriele, additional, Gattoni, Elisabetta, additional, Botta, Mario, additional, and Lombardi, Grazia, additional
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- 2012
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36. In Vitro and In Vivo Activity of a Novel Locked Nucleic Acid (LNA)-Inhibitor-miR-221 against Multiple Myeloma Cells.
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Di Martino, Maria Teresa, Gullà, Annamaria, Gallo Cantafio, Maria Eugenia, Altomare, Emanuela, Amodio, Nicola, Leone, Emanuela, Morelli, Eugenio, Lio, Santo Giovanni, Caracciolo, Daniele, Rossi, Marco, Frandsen, Niels M., Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
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MULTIPLE myeloma treatment ,ANTISENSE nucleic acids ,OLIGONUCLEOTIDES ,PLASMA cells ,RNA interference ,CANCER genetics - Abstract
Background & Aim: The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM) patients harboring the t(4;14) translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA)-Inhibitor-miR-221 (LNA-i-miR-221) specifically designed for systemic delivery. Methods: In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID) mice bearing t(4;14) MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs. Results: In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14)-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14) MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments. Conclusions: LNA-i-miR-221 is a highly stable, effective agent against t(4;14) MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA-i-miR-221 for the treatment of MM. [ABSTRACT FROM AUTHOR]
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- 2014
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37. Th17 Cells Targeting By MiR-21 Inhibitor Impairs Multiple Myeloma Related Bone Disease
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Rossi, Marco, Altomare, Emanuela, Amodio, Nicola, Di Martino, Maria Teresa, Gaspari, Marco, Taverna, Domenico, Scumaci, Domenica, Conforti, Francesco, Caracciolo, Daniele, Botta, Cirino, Federico, Cinzia, Gullà, Annamaria, Morelli, Eugenio, Scionti, Francesca, Arbitrio, Mariamena, Critelli, Paola, Neri, Antonino, Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
- Abstract
Bone disease (BD) represents a hallmark of multiple myeloma (MM), characterized by classical osteolytic lesions and/or osteoporosis, that can be life threatening and contribute to poor outcomes. The complex interplay among MM conditioned bone effectors such as MM cells, osteoclasts (OCLs) and osteoblasts within BM microenvironment (BMM) supports MMBD. Several studies have shown that the extent of BD is tightly correlated to Th17 cells development and maintenance. Th17 secrete pro OCL cytokines such as RANKL, TNF, and IL-17, contributing to MMBD development. Recent findings showed that microRNAs (miRNAs) are involved in MMBD. MiRNAs are short non-coding RNAs that regulate gene expression at a post transcriptional level. Among others, miR-21 is involved in Th17 differentiation by targeting SMAD-7, a negative regulator of TGF-β signaling, promoting the activation of SMAD-2/3, suppressing IL-2 expression, and ultimately enhancing the activity of the TGF-β signaling pathway. Taken together, these data support a therapeutic strategy of miR-21 targeting to ameliorate MMBD through Th17 inhibition. We have previously demonstrated that miR-21 activity within BMM plays a crucial role in bone resorption/apposition balance through PIAS3 suppression and STAT3 dependent RANKL transcription in BM stromal cells. In the present study, we sought to evaluate the role of miR-21 in Th17 mediated BD. We enriched Th17 from BM CD4+CCR6+T cells and evaluated miR-21 levels. We found increased miR-21 in MM derived Th17 (MMTh17) as compared to controls, supporting the relevance of miR-21 in MMTh17. To further explore the mechanisms of miR-21 activity in Th17 function, freshly isolated naïve CD4+T cells were differentiated from healthy donors into Th17 along 18 days of culture in the presence of polarizing cytokines. At the end of culture, T cells expressed the Th17 full maturation markers RORC and IL17. As a model of MMBD in vitro, OCL resorptive activity was evaluated on dentine discs with/without Th17 freshly isolated from MM patients or differentiated in vitro. In both cases, Th17 promoted potent OCL mediated dentin pits generation as compared to controls. To counteract miR-21 activity, we electroporated naïve CD4+T cells with miR-21 inhibitor (miR21i) or scramble control mirna before starting Th17 differentiation culture. MiR-21 expression levels were assessed by rt pcr before and at the end of differentiation culture to ascertain its effective inhibition. To map signaling pathways differences elicited by miR21i-Th17, we performed a mass spectrometry-based quantitative phosphoproteomics analysis. 1134 phosphorylated proteins were identified, with 386 significant changes as compared to controls. The global-pairwise-normalized data underwent to Ingenuity Pathway Analysis (IPA). Interestingly, analysis showed a generally higher level of phosphoserine sites and top canonical pathways affected by miR-21 inhibition included PI3K/AKT and 14-3-3 Signaling. Among Th17 potential regulators, enhanced activity of PDCD4, STAT1, MINK1 and FOXO1 were observed, while ITGAL showed reduced activity. On these bases, we performed WB to validate IPA analysis and explored additional widely acknowledged Th17 regulators. Upon miR-21i treatment, the expression of PDCD4 and FOXO1 were significantly increased while lower levels of RORC were observed. Furthermore, PIAS3 and TBX21 were significantly upregulated in the presence of miR-21 antagonism. STAT3 is a master transcription factor for Th17 upon IL-6 stimulation. As PIAS3 and PDCA4 negatively regulate STAT3, we checked phospho-STAT3 expression and found it downregulated as expected. Overall, these data indicated that Th17 differentiation was impaired by miR-21i. In the second set of experiments, we aimed to evaluate Th17 functional impairment by miR-21 antagonism in MMBD. OCLs were plated with dentine discs and exposed to either Th17 alone, miR21i-Th17, or RANKL/MCSF cytokine alone as positive control. Dentine pits and areas were significantly lower in the presence of miR21i-Th17 as compared to Th17 alone and positive control (Fig.1). These data indicated that miR-21 antagonism negatively regulates Th17 mediated OCL activity and support the role of miR-21 inhibition as an innovative treatment tool in MMBD.
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- 2017
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38. Synthetic MiR-29b Mimics Potentiate Dendritic-Cell Based Immunotherapy Against Multiple Myeloma In Vitroand In Vivo
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Botta, Cirino, Rossi, Marco, Pitari, Maria Rita, Gullà, Annamaria, Del Giudice, Teresa, Morelli, Eugenio, Iuliano, Eleonora, Altomare, Emanuela, Amodio, Nicola, Di Martino, Maria Teresa, Correale, Pierpaolo, Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
- Abstract
Dendritic cells (DCs) are potent antigen presenting cells that regulate the development of both innate and adaptive immune responses. According to their maturation status, DCs may ignite immune response or induce immune tolerance. Indeed, immature DCs (iDCs) present low levels of costimulatory molecules such as CD80 and CD86, and high levels of tolerogenic molecules such as B7H3. Upon exposure to maturation stimuli, DCs upregulate CD83 on their surface and gain the competence of stimulating T cell response. An efficient maturation is crucial for the generation of a specific cytotoxic T lymphocyte response, specially against cancer. However, recent reports have shown that Multiple Myeloma (MM) milieucan recruit DCs and reprogram them to sustain growth and survival of MM cells and protect them against immune response. Therapeutic approaches to restore DC functions rely on the identification of the pathways that are directly involved in induction of tolerance. Emerging evidence supports the role of microRNAs (miRNA) in the regulation of immune response and DC function. Among others, the miR-29 family seems to be involved in the modulation of NK activity, of Th1/Th2 phenotype switch and of DC differentiation from monocyte precursors. Besides, miR-29b targets and inhibits different and crucial immune-modulatory molecules such as B7H3, VEGF and IL-4. These findings suggest that miR-29 may play an important role in the multifaceted interplay between tumor cells and host's immune system. To address this hypothesis, we generated iDCs from CD14+ monocytes of healthy donors and co-cultured them with: i) allogeneic (allo-) lymphocytes; ii) VEGF and IL-6 producing MM cells (RPMI8226 and U266); iii) allo-lymphocyte and MM cells. We found a consistent increase of miR-29b expression by RT-PCR during differentiation and maturation of DCs induced by allo-lymphocytes. However, when immature DCs were co-cultured with MM cells +/- allo-lymphocytes, a significant 3-fold reduction of miR-29b levels (p= 0.02) was observed (fig 1). This event occurred together with the absence of maturation markers, the persistence of high levels of B7H3 on the cell surface and with a raise in VEGF, IL-10, and IFN-gamma levels in the supernatant, confirming the MM-dependent impairment of the physiological DC maturation process. This latter concept was supported by the finding of increased number of CD4+CD25+Foxp3+T-regs in the DC/MM cell/allo-lymphocyte co-cultures as compared to the DC/allo-lymphocyte co-cultures (p= 0.05). To promote the recovery from the MM related immune-bias, we transiently transfected iDCs with miR-29b (29b-DCs) mimics or with a negative control (NC-DCs). We observed improved DC maturation (82.46% versus39.89% of CD11c+/CD83+/CD86+ cells), reduced expression of B7H3 (33% reduction in MFI) and reduction of the T-reg number in 29b-DC/MM cell/allo-lymphocyte co-cultures as compared to NC-DC/MM cell/allo-lymphocyte co-culture. To investigate whether 29b-DCs were able to promote a specific CTL response against MM cells in vivo, we engrafted NOD/SCID γ chain-null mice with peripheral blood mononuclear cells (PBMCs) from HLA-A2+ healthy donors. DCs from the same donor were differentiated, transfected with either miR-29b or NC and then co-cultured with U266 for 48h. Mice were then vaccinated twice with either 29b-DCs or NC-DCs. Two weeks following the first injection, CD3+ human lymphocytes were recovered from mouse spleens (CD3 hu-splenocytes). We found an increased CD8/CD4 ratio in the CD3 hu-splenocytes collected from the 29b-DCs treated mouse as compared to control. To assess the capability of CD3+ hu-splenocytes to selectively kill U266 cells, we kept CD3 lymphocytes in culture in the presence of IL-15 for 48h. Then, we carried a cytotoxicity assay against U266 cell target. The highest specific lysis was attained with miR-29b DC primed CD3 hu-splenocytes (fig.2, p=0.03).
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- 2013
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39. In Vitroand VivoActivity Against Multiple Myeloma Cells Of a Novel Locked Nucleic Acid (LNA)-Mir-221 Inhibitor
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Di Martino, Maria Teresa, Gullà, Annamaria, Gallo Cantafio, Maria Eugenia, Altomare, Emanuela, Amodio, Nicola, Leone, Emanuela, Lio, Santo Giovanni, Morelli, Eugenio, Caracciolo, Daniele, Botta, Cirino, Neri, Antonino, Frandsen, Niels M, Tagliaferri, Pierosandro, and Tassone, Pierfrancesco
- Abstract
miR-221/222 are two highly homologous microRNAs (miRNAs), encoded in tandem on the chromosome X, whose up-regulation has been found in several malignancies and are thought to promote cell proliferation via down-regulation of p27 and/or p57, two negative regulators of G1 to S phase cell cycle progression. We demonstrated up-regulation of both miRNAs in malignant plasma cells (PCs) from multiple myeloma (MM) patients belonging to distinct TC (translocation/Cyclin) groups, including TC2 and TC4. A rising body of evidence suggests that silencing miRNAs with oncogenic potential could represent a novel approach for human cancer therapy. We previously demonstrated that silencing miR-221/222 exerts significant anti-MM activity and triggers canonical targets in vitroand in vivo. Here, in the aim to progress to clinical translation of our proof-of-principle findings, we investigated the anti-tumor activity and the appropriateness for systemic delivery of a novel and originally designed LNA-miR-221, a 13-mer antisense miR-221 inhibitor, which took advantage of locked nucleic acid (LNA) technology and phosphorothioate backbone chemistry for increasing affinity for miR-221 and nuclease resistance. We found that enforced ectopic expression of LNA-miR-221 in t(4;14) MM cells significantly inhibited growth and survival of MM cells in vitro. In treated cells, we detected knock down of miR-221/222 together and increased levels of both p27Kip1 mRNA and protein. Specific activity of this LNA-miR-221 inhibitor was confirmed by the use of a 3'UTR reporter (luciferase renilla/firefly) constructs containing, miR-221 target site. This construct was co-transfected either with miR-221/222 mimics or LNA-miR-221 inhibitor into MM cells. As predicted, a reduced luciferase activity was detected in miR-221/222 mimics co-transfected cells with each 3'UTR reporter plasmid, while increase luciferase activity was measured in MM cells co-transfected LNA-miR-221 inhibitors indicating an efficient and stable binding to the miRNA target sequence. Importantly, we evaluated the systemic delivery of the LNA-miR-221 inhibitor with saline solution vehicle alone by intraperitoneal or intravenous injection route against MM xenografts in SCID/NOD mice. Significant anti-tumor activity was achieved after 2 weeks of treatment at similar extent by both injection routes. Retrieved tumors from treated animals showed efficient inhibition of miR-221/222, as demonstrated by increased levels of p27Kip1 protein in vivo. H&E staining and immunohistochemical analysis showed wide necrosis areas, reduced Ki67 and a significant increase of p27Kip1 cytoplasmic expression in retrieved tumors from LNA-miR-221 inhibitor-treated mice. No changes in mice behavior or organ toxicity were observed in treated mice. Taken together these findings support the rationale for development of this novel and highly efficient LNA-miR-221 inhibitor as a promising anti-MM drug in subsequent primate toxicology studies. Supported by the Italian Association for Cancer Research (AIRC), PI: PT. “Special Program Molecular Clinical Oncology - 5 per mille” n. 9980, 2010/15.
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- 2013
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40. Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia
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Pierpaolo Correale, Andrea Ghelli Luserna di Rorà, Francesco Conforti, Gaetanina Golino, Caterina Riillo, Andrea Biondi, Massimo Martino, Giada Juli, Francesca Scionti, Pierfrancesco Tassone, Daniele Caracciolo, Emanuela Altomare, Gabriella Talarico, Eugénie Duroyon, Beatrice Belmonte, Nicoletta Polerà, Ludovic Lhermitte, Chiara Buracchi, Marco Rossi, Vahid Asnafi, Andrea Ballerini, Katia Grillone, Simona Sestito, Markus Hildinger, Greta Alampi, Cirino Botta, Maria Eugenia Gallo Cantafio, Maria Teresa Di Martino, Anna Maria Ferrari, Antonio Giordano, Mariamena Arbitrio, Pierosandro Tagliaferri, Licia Pensabene, Alessandro Gulino, Daniela Concolino, Giovanni Martinelli, Michelangelo Iannone, Claudio Tripodo, Giuseppe Gaipa, Caracciolo, Daniele, Riillo, Caterina, Ballerini, Andrea, Gaipa, Giuseppe, Lhermitte, Ludovic, Rossi, Marco, Botta, Cirino, Duroyon, Eugénie, Grillone, Katia, Gallo Cantafio, Maria Eugenia, Buracchi, Chiara, Alampi, Greta, Gulino, Alessandro, Belmonte, Beatrice, Conforti, Francesco, Golino, Gaetanina, Juli, Giada, Altomare, Emanuela, Polerà, Nicoletta, Scionti, Francesca, Arbitrio, Mariamena, Iannone, Michelangelo, Martino, Massimo, Correale, Pierpaolo, Talarico, Gabriella, Ghelli Luserna di Rorà, Andrea, Ferrari, Anna, Concolino, Daniela, Sestito, Simona, Pensabene, Licia, Giordano, Antonio, Hildinger, Marku, Di Martino, Maria Teresa, Martinelli, Giovanni, Tripodo, Claudio, Asnafi, Vahid, Biondi, Andrea, Tagliaferri, Pierosandro, Tassone, Pierfrancesco, Caracciolo, D, Riillo, C, Ballerini, A, Gaipa, G, Lhermitte, L, Rossi, M, Botta, C, Duroyon, E, Grillone, K, Cantafio, M, Buracchi, C, Alampi, G, Gulino, A, Belmonte, B, Conforti, F, Golino, G, Juli, G, Altomare, E, Polera, N, Scionti, F, Arbitrio, M, Iannone, M, Martino, M, Correale, P, Talarico, G, Di Rora, A, Ferrari, A, Concolino, D, Sestito, S, Pensabene, L, Giordano, A, Hildinger, M, Di Martino, M, Martinelli, G, Tripodo, C, Asnafi, V, Biondi, A, Tagliaferri, P, and Tassone, P
- Subjects
Cytotoxicity, Immunologic ,Cancer Research ,T-Lymphocytes ,Mice, SCID ,afucosylated monoclonal antibody ,Lymphocyte Activation ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Epitopes ,Jurkat Cells ,Antineoplastic Agents, Immunological ,Antibody Specificity ,Mice, Inbred NOD ,antigens ,Antibodies, Bispecific ,Tumor Microenvironment ,Immunology and Allergy ,antibodies ,hematologic neoplasms ,RC254-282 ,Antibody-dependent cell-mediated cytotoxicity ,Leukosialin ,bispecific T-cell engagers ,medicine.diagnostic_test ,biology ,hematological malignancie ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.anatomical_structure ,antibodie ,Oncology ,translational medical research ,Molecular Medicine ,Immunohistochemistry ,Female ,immunotherapy ,Antibody ,T-ALL ,T-cell engagers ,T-cell acute lymphoblastic leukemia ,medicine.drug_class ,T cell ,Immunology ,Settore MED/08 - Anatomia Patologica ,Monoclonal antibody ,Antibodies, Monoclonal, Humanized ,Flow cytometry ,T Acute Lymphoblastic Leukemia ,antigen ,Antigen ,Phagocytosis ,medicine ,Animals ,Humans ,hematological malignancies ,Cell Proliferation ,Pharmacology ,T-cell engager ,business.industry ,neoplasm ,translational research ,Basic Tumor Immunology ,Xenograft Model Antitumor Assays ,Cancer research ,biology.protein ,business ,hematologic neoplasm - Abstract
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.MethodsUMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv)2 constructs with bivalent (2+2) or monovalent (2+1) CD3ε arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL.ResultsAmong 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo.ConclusionAltogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.
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- 2021
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41. Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro
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Valerio Scotti, Pierosandro Tagliaferri, Cataldo Bianco, Roberto Bianco, Giulia Marvaso, Lavinia Raimondi, Valter Agosti, Agnese Barone, Michele Caraglia, Angela Lombardi, Pierfrancesco Tassone, Emanuela Altomare, Nicola Amodio, Marvaso, Giulia, Barone, Agnese, Amodio, Nicola, Raimondi, Lavinia, Agosti, Valter, Altomare, Emanuela, Scotti, Valerio, Lombardi, Angela, Bianco, Roberto, Bianco, Cataldo, Caraglia, Michele, Tassone, Pierfrancesco, and Tagliaferri, Pierosandro
- Subjects
FTY720 ,Cancer Research ,Ceramide ,Radiation-Sensitizing Agents ,Sphingosine kinase ,Apoptosis ,Breast Neoplasms ,Pharmacology ,Biology ,Radiation Tolerance ,Resting Phase, Cell Cycle ,G0 Phase ,chemistry.chemical_compound ,Breast cancer ,Sphingosine ,hemic and lymphatic diseases ,Cell Line, Tumor ,Autophagy ,medicine ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Radiation-Sensitizing Agent ,Caspase 7 ,Caspase 3 ,Fingolimod Hydrochloride ,Akt ,Apoptosi ,Lipid signaling ,medicine.disease ,Propylene Glycol ,Radiation therapy ,Erk ,Oncology ,chemistry ,Propylene Glycols ,Cancer cell ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor ,Breast Neoplasm ,Human ,Research Paper - Abstract
Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.
- Published
- 2014
42. Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma.
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Caracciolo D, Scionti F, Juli G, Altomare E, Golino G, Todoerti K, Grillone K, Riillo C, Arbitrio M, Iannone M, Morelli E, Amodio N, Di Martino MT, Rossi M, Neri A, Tagliaferri P, and Tassone P
- Subjects
- Apoptosis, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA End-Joining Repair, Genomic Instability, Humans, Multiple Myeloma drug therapy, Multiple Myeloma genetics
- Abstract
Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.
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- 2021
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43. DMET TM Genotyping: Tools for Biomarkers Discovery in the Era of Precision Medicine.
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Agapito G, Settino M, Scionti F, Altomare E, Guzzi PH, Tassone P, Tagliaferri P, Cannataro M, Arbitrio M, and Di Martino MT
- Abstract
The knowledge of genetic variants in genes involved in drug metabolism may be translated into reduction of adverse drug reactions, increase of efficacy, healthcare outcomes improvement and economic benefits. Many high-throughput tools are available for the genotyping of Single Nucleotide Polymorphisms (SNPs) known to be related to drugs and xenobiotics metabolism. DMET
TM platform represents an example of SNPs panel to discover biomarkers correlated to efficacy or toxicity in common and rare diseases. The difficulty in analyzing the mole of information generated by DMETTM platform led to the development and implementation of algorithms and tools for statistical and data mining analysis. These softwares allow efficient handling of the omics data to validate the explorative SNPs identified by DMET assay and to correlate them with drug efficacy, toxicity and/or cancer susceptibility. In this review we present a suite of bioinformatic frameworks for the preprocessing and analysis of DMET-SNPs data. In particular, we introduce a workflow that uses the GenoMetric Query Language, a high-level query language specifically designed for genomics, able to query public datasets (such as ENCODE, TCGA, GENCODE annotation dataset, etc.) as well as to combine them with private datasets (e.g., output from Affymetrix® DMETTM Platform).- Published
- 2020
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44. Polymorphic Variants in NR1I3 and UGT2B7 Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case-Control Study.
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Arbitrio M, Scionti F, Altomare E, Di Martino MT, Agapito G, Galeano T, Staropoli N, Iuliano E, Grillone F, Fabiani F, Caracciolo D, Cannataro M, Arpino G, Santini D, Tassone P, and Tagliaferri P
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- Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Biomarkers, Pharmacological analysis, Case-Control Studies, Constitutive Androstane Receptor, Female, Humans, Middle Aged, Outcome Assessment, Health Care, Pharmacogenomic Testing methods, Polymorphism, Single Nucleotide, Prognosis, Breast Neoplasms diagnosis, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Docetaxel administration & dosage, Docetaxel adverse effects, Glucuronosyltransferase genetics, Paclitaxel administration & dosage, Paclitaxel adverse effects, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases genetics, Peripheral Nervous System Diseases prevention & control, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
Taxane-related peripheral neuropathy (TrPN) is a dose-limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug-metabolizing enzyme and transporter microarray platform, in a retrospective case-control study, the correlation between ADME polymorphic variants and grades ≥ 2-3-TrPN was investigated. In a breast cancer (BC) training set, five single-nucleotide polymorphisms in NR1I3 and UDP-glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2-3-TrPN protection. By receiver operating characteristic curves, the grades ≥ 2-3-TrPN-related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel-TrPN and UGT2B7 to docetaxel-TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2019
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