المؤلفون: Liguoro, Domenico, Frigerio, Rachele, Ortolano, Arianna, Sacconi, Andrea, Acunzo, Mario, Romano, Giulia, Nigita, Giovanni, Bellei, Barbara, Madonna, Gabriele, Capone, Mariaelena, Ascierto, Paolo Antonio, Mancini, Rita, Ciliberto, Gennaro, Fattore, Luigi

المساهمون: Liguoro, Domenico, Frigerio, Rachele, Ortolano, Arianna, Sacconi, Andrea, Acunzo, Mario, Romano, Giulia, Nigita, Giovanni, Bellei, Barbara, Madonna, Gabriele, Capone, Mariaelena, Ascierto, Paolo Antonio, Mancini, Rita, Ciliberto, Gennaro, Fattore, Luigi

مصطلحات موضوعية: melanoma, microRNA, targeted therapies

الوصف: Therapy of melanoma has improved dramatically over the last years thanks to the development of targeted therapies (MAPKi) and immunotherapies. However, drug resistance continues to limit the efficacy of these therapies. Our research group has provided robust evidence as to the involvement of a set of microRNAs in the development of resistance to target therapy in BRAF-mutated melanomas. Among them, a pivotal role is played by the oncosuppressor miR-579-3p. Here we show that miR-579-3p and the microphthalmia-associated transcription factor (MITF) influence reciprocally their expression through positive feedback regulatory loops. In particular we show that miR-579-3p is specifically deregulated in BRAF-mutant melanomas and that its expression levels mirror those of MITF. Luciferase and ChIP studies show that MITF is a positive regulator of miR-579-3p, which is located in the intron 11 of the human gene ZFR (Zink-finger recombinase) and is co-transcribed with its host gene. Moreover, miR-579-3p, by targeting BRAF, is able to stabilize MITF protein thus inducing its own transcription. From biological points of view, early exposure to MAPKi or, alternatively miR-579-3p transfection, induce block of proliferation and trigger senescence programs in BRAF-mutant melanoma cells. Finally, the long-term development of resistance to MAPKi is able to select cells characterized by the loss of both miR-579-3p and MITF and the same down-regulation is also present in patients relapsing after treatments. Altogether these findings suggest that miR-579-3p/MITF interplay potentially governs the balance between proliferation, senescence and resistance to therapies in BRAF-mutant melanomas.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38472212; volume:15; issue:3; firstpage:1; lastpage:11; numberofpages:11; journal:CELL DEATH & DISEASE; https://hdl.handle.net/11573/1705216Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85187522115

الإتاحة: https://doi.org/10.1038/s41419-024-06580-2Test
https://hdl.handle.net/11573/1705216Test

المؤلفون: Fattore, Luigi, Cafaro, Giordana, Di Martile, Marta, Campani, Virginia, Sacconi, Andrea, Liguoro, Domenico, Marra, Emanuele, Bruschini, Sara, Stoppoloni, Daniela, Cirombella, Roberto, De Nicola, Francesca, Pallocca, Matteo, Ruggiero, Ciro F, Castaldo, Vittorio, Catizone, Angiolina, Del Bufalo, Donatella, Viglietto, Giuseppe, Vecchione, Andrea, Blandino, Giovanni, Aurisicchio, Luigi, Fanciulli, Maurizio, Ascierto, Paolo A, De Rosa, Giuseppe, Mancini, Rita, Ciliberto, Gennaro

المساهمون: Fattore, Luigi, Cafaro, Giordana, Di Martile, Marta, Campani, Virginia, Sacconi, Andrea, Liguoro, Domenico, Marra, Emanuele, Bruschini, Sara, Stoppoloni, Daniela, Cirombella, Roberto, De Nicola, Francesca, Pallocca, Matteo, Ruggiero, Ciro F, Castaldo, Vittorio, Catizone, Angiolina, Del Bufalo, Donatella, Viglietto, Giuseppe, Vecchione, Andrea, Blandino, Giovanni, Aurisicchio, Luigi, Fanciulli, Maurizio, Ascierto, Paolo A, De Rosa, Giuseppe, Mancini, Rita, Ciliberto, Gennaro

مصطلحات موضوعية: melanoma, oncoMir, BRAF

الوصف: BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36418472; info:eu-repo/semantics/altIdentifier/wos/WOS:000886818700001; volume:42; issue:4; firstpage:293; lastpage:307; numberofpages:15; journal:ONCOGENE; https://hdl.handle.net/11573/1661031Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85142445757

الإتاحة: https://doi.org/10.1038/s41388-022-02547-9Test
https://hdl.handle.net/11573/1661031Test

المؤلفون: Castaldo, Vittorio, Minopoli, Michele, Di Modugno, Francesca, Sacconi, Andrea, Liguoro, Domenico, Frigerio, Rachele, Ortolano, Arianna, Di Martile, Marta, Gesualdi, Luisa, Madonna, Gabriele, Capone, Mariaelena, Cirombella, Roberto, Catizone, Angiolina, Del Bufalo, Donatella, Vecchione, Andrea, Carriero, Maria Vincenza, Ascierto, Paolo Antonio, Mancini, Rita, Fattore, Luigi, Ciliberto, Gennaro

المساهمون: Associazione Italiana per la Ricerca sul Cancro, Lazio Innova, Ministero dell’Istruzione, dell’Università e della Ricerca, Ministero della Salute, Lega italiana per la lotta contro i tumori

المصدر: Journal of Experimental & Clinical Cancer Research ; volume 42, issue 1 ; ISSN 1756-9966

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Background BRAF-mutant melanoma patients benefit from the combinatorial treatments with BRAF and MEK inhibitors. However, acquired drug resistance strongly limits the efficacy of these targeted therapies in time. Recently, many findings have underscored the involvement of microRNAs as main drivers of drug resistance. In this context, we previously identified a subset of oncomiRs strongly up-regulated in drug-resistant melanomas. In this work, we shed light on the molecular role of two as yet poorly characterized oncomiRs, miR-4443 and miR-4488. Methods Invasion and migration have been determined by wound healing, transwell migration/invasion assays and Real Time Cell Analysis (RTCA) technology. miR-4488 and miR-4443 have been measured by qRT-PCR. Nestin levels have been tested by western blot, confocal immunofluorescence, immunohistochemical and flow cytometry analyses. Results We demonstrate that the two oncomiRs are responsible for the enhanced migratory and invasive phenotypes, that are a hallmark of drug resistant melanoma cells. Moreover, miR-4443 and miR-4488 promote an aberrant cytoskeletal reorganization witnessed by the increased number of stress fibers and cellular protrusions-like cancer cell invadopodia. Mechanistically, we identified the intermediate filament nestin as a molecular target of both oncomiRs. Finally, we have shown that nestin levels are able to predict response to treatments in melanoma patients. Conclusions Altogether these findings have profound translational implications in the attempt i) to develop miRNA-targeting therapies to mitigate the metastatic phenotypes of BRAF-mutant melanomas and ii) to identify novel biomarkers able to guide clinical decisions. Graphical Abstract

الإتاحة: https://doi.org/10.1186/s13046-023-02878-9Test

المؤلفون: Blandino, Giovanni, Dinami, Roberto, Marcia, Marco, Anastasiadou, Eleni, Ryan, Brid M., Palcau, Alina Catalina, Fattore, Luigi, Regazzo, Giulia, Sestito, Rosanna, Loria, Rossella, Díaz Méndez, Ana Belén, Cappelletto, Maria Chiara, Pulito, Claudio, Monteonofrio, Laura, Calin, George A., Sozzi, Gabriella, Cheong, Jit Kong, Aharonov, Ranit, Ciliberto, Gennaro

المصدر: Journal of Experimental & Clinical Cancer Research ; volume 42, issue 1 ; ISSN 1756-9966

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27–28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled “The New World of RNA diagnostics and therapeutics” highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer. This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment. In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov).

الإتاحة: https://doi.org/10.1186/s13046-023-02752-8Test

المؤلفون: Lazzarini, Elisabetta, Silvestris, Domenico Alessandro, Benvenuto, Giuseppe, Osti, Daniela, Fattore, Luigi, Paterra, Rosina, Finocchiaro, Gaetano, Malatesta, Paolo, Daga, Antonio, Gallotti, Alberto L., Galli, Rossella, Pelicci, Giuliana, Tesei, Anna, Bedeschi, Martina, Pallini, Roberto, Pasqualini, Lorenza, Romualdi, Chiara, Gallo, Angela, Ricci-Vitiani, Lucia, Indraccolo, Stefano

المساهمون: Alleanza Contro il Cancro, Università degli Studi di Padova

المصدر: Journal of Neuro-Oncology ; volume 163, issue 1, page 47-59 ; ISSN 0167-594X 1573-7373

مصطلحات موضوعية: Cancer Research, Neurology (clinical), Neurology, Oncology

الوصف: Purpose Patient-derived cancer cell lines can be very useful to investigate genetic as well as epigenetic mechanisms of transformation and to test new drugs. In this multi-centric study, we performed genomic and transcriptomic characterization of a large set of patient-derived glioblastoma (GBM) stem-like cells (GSCs). Methods 94 (80 I surgery/14 II surgery) and 53 (42 I surgery/11 II surgery) GSCs lines underwent whole exome and trascriptome analysis, respectively. Results Exome sequencing revealed TP53 as the main mutated gene (41/94 samples, 44%), followed by PTEN (33/94, 35%), RB1 (16/94, 17%) and NF1 (15/94, 16%), among other genes associated to brain tumors. One GSC sample bearing a BRAF p.V600E mutation showed sensitivity in vitro to a BRAF inhibitor. Gene Ontology and Reactome analysis uncovered several biological processes mostly associated to gliogenesis and glial cell differentiation, S − adenosylmethionine metabolic process, mismatch repair and methylation. Comparison of I and II surgery samples disclosed a similar distribution of mutated genes, with an overrepresentation of mutations in mismatch repair, cell cycle, p53 and methylation pathways in I surgery samples, and of mutations in receptor tyrosine kinase and MAPK signaling pathways in II surgery samples. Unsupervised hierarchical clustering of RNA-seq data produced 3 clusters characterized by distinctive sets of up-regulated genes and signaling pathways. Conclusion The availability of a large set of fully molecularly characterized GCSs represents a valuable public resource to support the advancement of precision oncology for the treatment of GBM.

الإتاحة: https://doi.org/10.1007/s11060-023-04287-6Test

المؤلفون: Bruschini, Sara, Pallocca, Matteo, Sperandio, Eleonora, D'Ambrosio, Lorenzo, Ascenzi, Francesca, De Vitis, Claudia, Salvati, Valentina, Esposito, Antonella, Di Martino, Simona, De Nicola, Francesca, Paolini, Francesca, Fattore, Luigi, Alessandrini, Gabriele, Facciolo, Francesco, Foddai, Maria Laura, Bassi, Massimiliano, Venuta, Federico, D'Ascanio, Michela, Ricci, Alberto, D' Andrilli, Antonio, Napoli, Christian, Aurisicchio, Luigi, Fanciulli, Maurizio, Rendina, Erino Angelo, Ciliberto, Gennaro, Mancini, Rita

المساهمون: Bruschini, Sara, Pallocca, Matteo, Sperandio, Eleonora, D'Ambrosio, Lorenzo, Ascenzi, Francesca, De Vitis, Claudia, Salvati, Valentina, Esposito, Antonella, Di Martino, Simona, De Nicola, Francesca, Paolini, Francesca, Fattore, Luigi, Alessandrini, Gabriele, Facciolo, Francesco, Foddai, Maria Laura, Bassi, Massimiliano, Venuta, Federico, D'Ascanio, Michela, Ricci, Alberto, D' Andrilli, Antonio, Napoli, Christian, Aurisicchio, Luigi, Fanciulli, Maurizio, Rendina, Erino Angelo, Ciliberto, Gennaro, Mancini, Rita

مصطلحات موضوعية: computational biology, lung neoplasm, macrophage, tumor escape, tumor microenvironment

الوصف: Background: Immune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC. Methods: Mononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271). Results: Transcriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients. Conclusions: Our study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new ...

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35584864; info:eu-repo/semantics/altIdentifier/wos/WOS:000798224600002; volume:10; issue:5; journal:JOURNAL FOR IMMUNOTHERAPY OF CANCER; http://hdl.handle.net/11573/1634885Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85130301591

الإتاحة: https://doi.org/10.1136/jitc-2021-004239Test
http://hdl.handle.net/11573/1634885Test

المؤلفون: Fattore, Luigi, Cafaro, Giordana, Di Martile, Marta, Campani, Virginia, Sacconi, Andrea, Liguoro, Domenico, Marra, Emanuele, Bruschini, Sara, Stoppoloni, Daniela, Cirombella, Roberto, De Nicola, Francesca, Pallocca, Matteo, Ruggiero, Ciro F., Castaldo, Vittorio, Catizone, Angiolina, Del Bufalo, Donatella, Viglietto, Giuseppe, Vecchione, Andrea, Blandino, Giovanni, Aurisicchio, Luigi, Fanciulli, Maurizio, Ascierto, Paolo A., De Rosa, Giuseppe, Mancini, Rita, Ciliberto, Gennaro

المصدر: Oncogene ; volume 42, issue 4, page 293-307 ; ISSN 0950-9232 1476-5594

مصطلحات موضوعية: Cancer Research, Genetics, Molecular Biology

الوصف: BRAF-mutated melanoma relapsing after targeted therapies is an aggressive disease with unmet clinical need. Hence the need to identify novel combination therapies able to overcome drug resistance. miRNAs have emerged as orchestrators of non-genetic mechanisms adopted by melanoma cells to challenge therapies. In this context we previously identified a subset of oncosuppressor miRNAs downregulated in drug-resistant melanomas. Here we demonstrate that lipid nanoparticles co-encapsulating two of them, miR-199-5p and miR-204-5p, inhibit tumor growth both in vitro and in vivo in combination with target therapy and block the development of drug resistance. Mechanistically they act by directly reducing melanoma cell growth and also indirectly by hampering the recruitment and reprogramming of pro-tumoral macrophages. Molecularly, we demonstrate that the effects on macrophages are mediated by the dysregulation of a newly identified miR-204-5p-miR-199b-5p/CCL5 axis. Finally, we unveiled that M2 macrophages programs are molecular signatures of resistance and predict response to therapy in patients. Overall, these findings have strong translational implications to propose new combination therapies making use of RNA therapeutics for metastatic melanoma patients.

الإتاحة: https://doi.org/10.1038/s41388-022-02547-9Test
https://www.nature.com/articles/s41388-022-02547-9.pdfTest
https://www.nature.com/articles/s41388-022-02547-9Test

المؤلفون: Ruggiero, Ciro Francesco, Fattore, Luigi, Terrenato, Irene, Sperati, Francesca, Salvati, Valentina, Madonna, Gabriele, Capone, Mariaelena, Valenti, Fabio, Di Martino, Simona, Mandoj, Chiara, Liguoro, Domenico, Castaldo, Vittorio, Cafaro, Giordana, Simeone, Ester, Vanella, Vito, Russillo, Michelangelo, Conti, Laura, Cuda, Giovanni, Giannarelli, Diana, Ascierto, Paolo Antonio, Mancini, Rita, Ciliberto, Gennaro

المصدر: Theranostics ; volume 12, issue 17, page 7420-7430 ; ISSN 1838-7640

الإتاحة: https://doi.org/10.7150/thno.77761Test
https://www.thno.org/v12p7420.htmTest

المؤلفون: Nanda, Vashisht GY, Peng, Weiyi, Hwu, Patrick, Davies, Michael A, Ciliberto, Gennaro, Fattore, Luigi, Malpicci, Debora, Aurisicchio, Luigi, Ascierto, Paolo Antonio, Croce, Carlo M, Mancini, Rita, Spranger, Stefani, Gajewski, Thomas F, Wang, Yangyang, Ferrone, Soldano, Vanpouille-Box, Claire, Wennerberg, Erik, Pilones, Karsten A, Formenti, Silvia C, Demaria, Sandra, Tang, Haidong, Wang, Yang, Fu, Yang-Xin, Dummer, Reinhard, Puzanov, Igor, Tarhini, Ahmad, Chauvin, Joe-Marc, Pagliano, Ornella, Fourcade, Julien, Sun, Zhaojun, Wang, Hong, Sanders, Cindy, Kirkwood, John M, Chen, Tseng-hui Timothy, Maurer, Mark, Korman, Alan J, Zarour, Hassane M, Stroncek, David F, Huber, Veronica, Rivoltini, Licia, Thurin, Magdalena, Rau, Tilman, Lugli, Alessandro, Pagès, Franck, Camarero, Jorge, Sancho, Arantxa, Jommi, Claudio, de Coaña, Yago Pico, Wolodarski, Maria, Yoshimoto, Yuya, Gentilcore, Giusy, Poschke, Isabel, Masucci, Giuseppe V, Hansson, Johan, Kiessling, Rolf, Scognamiglio, Giosuè, Sabbatino, Francesco, Marino, Federica Zito, Anniciello, Anna Maria, Cantile, Monica, Cerrone, Margherita, Scala, Stefania, D’alterio, Crescenzo, Ianaro, Angela, Cirin, Giuseppe, Liguori, Giuseppina, Bott, Gerardo, Chapman, Paul B, Robert, Caroline, Larkin, James, Haanen, John B, Ribas, Antoni, Hogg, David, Hamid, Omid, Testori, Alessandro, Lorigan, Paul, Sosman, Jeffrey A, Flaherty, Keith T, Yue, Huibin, Coleman, Shelley, Caro, Ivor, Hauschild, Axel, McArthur, Grant A, Sznol, Mario, Callahan, Margaret K, Kluger, Harriet, Postow, Michael A, Gordan, RuthAnn, Segal, Neil H, Rizvi, Naiyer A, Lesokhin, Alexander, Atkins, Michael B, Burke, Matthew M, Ralabate, Amanda, Rivera, Angel, Kronenberg, Stephanie A, Agunwamba, Blessing, Ruisi, Mary, Horak, Christine, Jiang, Joel

المصدر: Journal of Translational Medicine. 14(Suppl 1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Cancer, Good Health and Well Being, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences

الوصف: MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunoscore task force: an update K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology Tilman Rau, Alessandro Lugli K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients Franck Pagès Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues K17 Nivolumab, the regulatory experience in immunotherapy Jorge Camarero, Arantxa Sancho K18 Evidence to optimize access for immunotherapies Claudio Jommi ORAL PRESENTATIONS Molecular and immuno-advances O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok Combination therapies O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts) Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi News in immunotherapy O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066 Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067 Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok Tumor microenvironment and biomarkers O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco O14 Immunological prognostic factors in stage III melanomas María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel POSTER PRESENTATIONS Molecular and immuno-advances P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto P6 HuR positively regulates migration of HTB63 melanoma cells Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris P10 New insights in mitochondrial metabolic reprogramming in melanoma Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris Combination therapies P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola News in immunotherapy P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe P16 Immunotherapy and hypophysitis: a case report Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi Tumor microenvironment and biomarkers P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile Other P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi P22 Epidemiological survey on related psychopathology in melanoma Valeria De Biasio, Vincenzo C. Battarra IMMUNOTHERAPY BRIDGE KEYNOTE SPEAKER PRESENTATIONS Immunotherapy beyond melanoma K19 Predictor of response to radiation and immunotherapy Silvia Formenti K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho K22 Anti-cancer immunity despite T cell “exhaustion” Speiser Daniel Immunotherapy in oncology (I-O): data from clinical trial K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) Vera Hirsh

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الوصول الحر: https://escholarship.org/uc/item/939406c2Test

المؤلفون: Fattore, Luigi, Malpicci, Debora, Marra, Emanuele, Belleudi, Francesca, Noto, Alessia, De Vitis, Claudia, Pisanu, Maria Elena, Coluccia, Pierpaolo, Camerlingo, Rosa, Roscilli, Giuseppe, Ribas, Antoni, Di Napoli, Arianna, Torrisi, Maria Rosaria, Aurisicchio, Luigi, Ascierto, Paolo Antonio, Mancini, Rita, Ciliberto, Gennaro

المصدر: Oncotarget. 6(28)

مصطلحات موضوعية: Cancer, Biotechnology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Blotting, Western, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Synergism, Epitopes, Humans, Indoles, MAP Kinase Kinase 1, Melanoma, Mice, Mutation, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Pyridones, Pyrimidinones, Receptor, ErbB-3, Sulfonamides, Vemurafenib, Xenograft Model Antitumor Assays, melanoma, BRAF/MEK inhibitors, ErbB3 activation, Anti-ErbB3 antibodies, in vivo regrowth impairment, Receptor, erbB-3, Oncology and Carcinogenesis

الوصف: Patients with metastatic melanoma bearing V600 mutations in BRAF oncogene clinically benefit from the treatment with BRAF inhibitors alone or in combination with MEK inhibitors. However, a limitation to such treatment is the occurrence of resistance. Tackling the adaptive changes helping cells survive from drug treatment may offer new therapeutic opportunities. Very recently the ErbB3 receptor has been shown to act as a central node promoting survival of BRAF mutated melanoma. In this paper we first demonstrate that ErbB3/AKT hyperphosphorylation occurs in BRAF mutated melanoma cell lines following exposure to BRAF and/or MEK inhibitors. This strongly correlates with increased transcriptional activation of its ligand neuregulin. Anti-ErbB3 antibodies impair the establishment of de novo cell resistance to BRAF inhibition in vitro. In order to more potently ablate ErbB3 activity we used a combination of two anti-ErbB3 antibodies directed against distinct epitopes of its extracellular domain. These two antibodies in combo with BRAF/MEK inhibitors potently inhibit in vitro cell growth and tumor regrowth after drug withdrawal in an in vivo xenograft model. Importantly, residual tumor masses from mice treated by the antibodies and BRAF/ERK inhibitors combo are characterized almost exclusively by large necrotic areas with limited residual areas of tumor growth. Taken together, our findings support the concept that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma.

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الوصول الحر: https://escholarship.org/uc/item/7hf2c5gqTest