16 results on '"Elia Cipriano"'
Search Results
2. Supplementary Tables S1-S5 from A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem–Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy
- Author
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Carla Boccaccio, Livio Trusolino, Andrea Bertotti, Paolo M. Comoglio, Enzo Medico, Sara E. Bellomo, Claudio Isella, Francesca De Bacco, Francesco Sassi, Francesca Orzan, Gigliola Reato, Elia Cipriano, Viola Bigatto, and Paolo Luraghi
- Abstract
Supplementary Table-S1: Somatic mutations in xenospheres Supplementary Table-S2: Pearson's correlation values between xenospheres' and xenopatients' gene expression profiles. Supplementary Table-S3: genes affected by copy number variations, as detected by WES in xenopsheres. Supplementary Table-S4: genes affected by somatic mutations, as detected by WES in xenopsheres. Supplementary Table-S5: total number of shared and private somatic mutations and copy number variations in matched xenospheres and xenopatients.
- Published
- 2023
3. Data from A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem–Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy
- Author
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Carla Boccaccio, Livio Trusolino, Andrea Bertotti, Paolo M. Comoglio, Enzo Medico, Sara E. Bellomo, Claudio Isella, Francesca De Bacco, Francesco Sassi, Francesca Orzan, Gigliola Reato, Elia Cipriano, Viola Bigatto, and Paolo Luraghi
- Abstract
Purpose: Patient-derived xenografts (“xenopatients”) of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures (“xenospheres”) was generated and characterized for response to targeted therapies.Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition.Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807–20. ©2017 AACR.See related commentary by Napolitano and Ciardiello, p. 727
- Published
- 2023
4. Data from MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
- Author
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Carla Boccaccio, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti, Timothy Perera, William M. Rideout, May Han, Elena Menietti, Francesca De Bacco, Viola Bigatto, Francesca Orzan, Francesco Sassi, Elia Cipriano, Gigliola Reato, and Paolo Luraghi
- Abstract
Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer–initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed “xenospheres,” were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts; like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, whereas those harboring wild-type RAS pathway genes (RASwt) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RASwt CCICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof-of-concept for concurrent targeting of these two pathways in the clinical setting. Cancer Res; 74(6); 1857–69. ©2014 AACR.
- Published
- 2023
5. Supplementary Methods from MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
- Author
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Carla Boccaccio, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti, Timothy Perera, William M. Rideout, May Han, Elena Menietti, Francesca De Bacco, Viola Bigatto, Francesca Orzan, Francesco Sassi, Elia Cipriano, Gigliola Reato, and Paolo Luraghi
- Abstract
PDF file - 121K
- Published
- 2023
6. Supplementary Figures 1 - 6 from MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
- Author
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Carla Boccaccio, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti, Timothy Perera, William M. Rideout, May Han, Elena Menietti, Francesca De Bacco, Viola Bigatto, Francesca Orzan, Francesco Sassi, Elia Cipriano, Gigliola Reato, and Paolo Luraghi
- Abstract
PDF file - 8193K, Supplementary Figure S1. Xensophere characterization. Supplementary Figure S2. EGF in Raswt xenosphere proliferation. Supplementary Figure S3. MET inhibition in xenospheres treated with FCM. Supplementary Figure S4. HGF dose-response in RASwt xenosphere viability. Supplementary Figure S5. M049 spheropatient treatment and HGF autocrine loop in M049 xenosphere. Supplementary Figure S6. CC-IC marker expression in M049 xenospheres and spheropatients treated with inhibitors.
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- 2023
7. Supplementary Tables 1 - 4 from MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
- Author
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Carla Boccaccio, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti, Timothy Perera, William M. Rideout, May Han, Elena Menietti, Francesca De Bacco, Viola Bigatto, Francesca Orzan, Francesco Sassi, Elia Cipriano, Gigliola Reato, and Paolo Luraghi
- Abstract
PDF file - 733K, Supplementary Table S1. Gene alterations in xenospheres. Supplementary Table S2. Cetuximab response in Raswt xenopatients and spheropatients. Supplementary Table S3. Tumor volumes and regression of M049-HGF spheropatients. Supplementary Table S4. List of primers used for gDNA sequencing and qPCR.
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- 2023
8. Walking difficulties and brainstem dysfunction: a case report of adult onset Leigh syndrome
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Elia Cipriano, Domizia Vecchio, Letizia Mazzini, Gionata Strigaro, Daniela Piga, Monica Sciacco, Giacomo Comi, Egidio Genovese, and Roberto Cantello
- Abstract
Introduction: Leigh syndrome a progressive, lethal, mitochondrial disease. Case Presentation: We report the case of an adult man in his 40s presenting to the Emergency Department showing: dysarthria, oculomotor limitations for downgaze and convergence, mild right hemiparesis with Babinski sign and absent lower limb tendon reflexes. He revealed about walking difficulties since the age of 20-25. Family history was unremarkable. A brain magnetic resonance showed diffuse white matter lesions involving the area around the third ventricle, the medulla oblongata, and the bilateral caudate and putamen without contrast enhancement. Conclusions: Polymerase-chain-reaction amplification of the mitochondrial genes, followed by direct sequencing, found a 10191T>C variant related to Leigh syndrome. Leigh syndrome mostly occurring mostly in childhood, there are only other 8 late-onset cases described sharing the same pathogenic variant. LS or subacute necrotizing encephalomyelopathy is a progressive, lethal, mitochondrial disease mostly occurring in childhood. Only other 8 late-onset cases share the same pathogenic variant, i.e. 10191T>C.
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- 2023
9. Reduced Admissions for Cerebrovascular Events during COVID-19 Outbreak in Italy
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Simona Sacco, Stefano Ricci, Raffaele Ornello, Paolo Eusebi, Luca Petraglia, Danilo Toni, Eugenia Rota, Gianluca Bruzzone, Lucia Testa, Roberta Bongioanni, Mara Rosso, Carmelo Labate, Roberto Tarletti, Roberto Cantello, Thomas Fleetwood, Fabio Melis, Daniele Imperiale, Salvatore Amarù, Monica Reggiani, Luigi Ruiz, Elia Cipriano, Delfina Ferrandi, Patrizia Julita, Liana Africa, Piero Meinieri, Maria Federica Grasso, Serena Servo, Roberto Cavallo, Gigliola Chianale, Andrea Naldi, Paolo Cerrato, Elisa Rubino, Alessia Giossi, Valentina Puglisi, Luisa Vinciguerra, Ignazio Santilli, Bianca Maria Bordo, Simona Marcheselli, Julia Bottini, Caterina Mariotto D’Alessandro, Giuseppe Micieli, Anna Cavallini, Isabella Canavero, Francesco Muscia, Graziamaria Nuzzaco, Alfonso Ciccone, Giorgio Silvestrelli, Andrea Salmaggi, Davide Sangalli, Carla Zanferrari, Simona Fanucchi, Michela Ranieri, Simone Beretta, Carlo Ferrarese, Francesco Pasini, Francesco Santangelo, Nicoletta Checcarelli, Sandro Beretta, Paola Bazzi, Massimo Camerlingo, Marcello Tognozzi, Giorgio Caneve, Alessandro Adami, Rocco Quatrale, Adriana Critelli, Luigi Bartolomei, Maela Masato, Francesco Perini, Antonella De Boni, Caterina Disco, Claudio Baracchini, Alessio Pieroni, Roberto Lerario, Monia Russo, Alberto Polo, Alessandra Danese, Luca Valentinis, Antonio Baldi, Simone Tonello, Francesco Paladin, Agnese Tonon, Bruno Bonetti, Manuel Cappellari, Francesco Teatini, Roberto Currò Dossi, Enrica Franchini, Bruno Giometto, Valeria Bignamini, Paolo Manganotti, Marcello Naccarato, Gian Luigi Gigli, Simone Lorenzut, Giovanni Merlino, Mariarosaria Valente, Michele Rana, Carolina Gentile, Tiziana Tassinari, Annalisa Sugo, Valentina Saia, Maurizio Balestrino, Alberto Coccia, Cinzia Finocchi, Franco Valzania, Maria Luisa Zedde, Giulia Toschi, Marco Longoni, Matteo Paolucci, Valeria Tugnoli, Pietro Querzani, Marina Padroni, Stefano Meletti, Guido Bigliardi, Maria Luisa Dall’Acqua, Andrea Zini, Mauro Gentile, Ludovica Migliaccio, Alberto Chiti, Rossana Tassi, Giuseppe Martini, Patrizia Nencini, Maria Lamassa, Michelangelo Mancuso, Giovanni Orlandi, Elena Ferrari, Roberto Marconi, Simone Gallerini, Vincenzo Groggia, Gino Volpi, Chiara Menichetti, Stefano Spolveri, Mauro Silvestrini, Giovanna Viticchi, Laura Buratti, Giuseppe Pelliccioni, Eleonora Potente, Tatiana Mazzoli, Erica Marsili, Silvia Cenciarelli, Antonella Picchioni, Franco Costantini, Carlo Colosimo, Maurizio Paciaroni, Valeria Caso, Maurizia Rasura, Mario Beccia, Nicola Falcone, Marisa Di Stefano, Emanuela Cecconi, Sabrina Anticoli, Francesca Romana Pezzella, Marilena Mangiardi, Maurizio Plocco, Maria Magarelli, Carlo Emanuele Saggese, Irene Berto, Maria Concetta Altavista, Cinzia Roberti, Marina Diomedi, Fabrizio Sallustio, Alessandro Rocco, Letizia Maria Cupini, Novella Bonaffini, Maria Vittoria De Angelis, Anna Digiovanni, Marianna Rispoli, Berardino Orlandi, Federica De Santis, Enrico Colangeli, Francesco Di Blasio, Caterina Di Carmine, Pierluigi Tocco, Maurizio Melis, Jessica Moller, Valeria Saddi, Antonio Manca, Antonio Baule, Antonello Caddeo, Nicola Iorio, Rosa Napoletano, Maria di Gregorio, Giampiero Volpe, Florindo D’Onofrio, Daniele Spitaleri, Leonardo Barbarini, Gaetano Barbagallo, Marcella Caggiula, Bonaventura Ardito, Domenico Di Noia, Pietro Di Viesti, Maurizio Angelo Leone, Vincenzo Inchingolo, Marco Petruzzellis, Federica Rizzo, Mariantonietta Savarese, Alfredo Petrone, Franco Galati, Luciano Arcudi, Damiano Branca, Paolo Aridon, Valentina Arnao, Rosa Musolino, Cristina Dell’Aera, Isabella Francalanza, Luigi Grimaldi, Matilde Gammino, Antonello Giordano, Giuseppe Zelante, Enzo Sanzaro, Antonio Gasparro, Sacco, Simona, Ricci, Stefano, Ornello, Raffaele, Eusebi, Paolo, Petraglia, Luca, Toni, Danilo, and paolo, aridon
- Subjects
disease outbreak ,Male ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Italy ,cerebral hemorrhage ,disease outbreaks ,incidence ,ischemic attack, transient ,0302 clinical medicine ,Epidemiology ,80 and over ,Medicine ,Thrombolytic Therapy ,Acute ischemic stroke ,Thrombectomy ,Aged, 80 and over ,Ischemic Attack ,Transient ,Incidence (epidemiology) ,Endovascular Procedures ,Middle Aged ,Hospitalization ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Settore MED/26 - Neurologia ,Female ,Cardiology and Cardiovascular Medicine ,Aged ,COVID-19 ,Cerebral Hemorrhage ,Humans ,Ischemic Attack, Transient ,Ischemic Stroke ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Revascularization ,Settore MED/26 ,03 medical and health sciences ,Advanced and Specialized Nursing ,business.industry ,Outbreak ,Emergency medicine ,Brief Reports ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Supplemental Digital Content is available in the text., Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71–0.80] P
- Published
- 2020
10. A young male with walking difficulties and subacute brainstem dysfunction: Adult-onset Leigh syndrome
- Author
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Giacomo P. Comi, Elia Cipriano, Daniela Piga, Letizia Mazzini, Egidio Genovese, Gionata Strigaro, Roberto Cantello, Monica Sciacco, and Domizia Vecchio
- Subjects
Pediatrics ,medicine.medical_specialty ,Neurology ,business.industry ,Medicine ,Neurology (clinical) ,Brainstem ,business ,Young male - Published
- 2021
11. A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem-Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy
- Author
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Sara Erika Bellomo, Gigliola Reato, Viola Bigatto, Enzo Medico, Carla Boccaccio, Paolo Luraghi, Andrea Bertotti, Livio Trusolino, Claudio Isella, Elia Cipriano, Francesca Orzan, Francesca De Bacco, Francesco Sassi, and Paolo M. Comoglio
- Subjects
0301 basic medicine ,Cancer Research ,Colorectal cancer ,BIOMARKERS ,Cetuximab ,Drug resistance ,Mice, SCID ,Biology ,COLORECTAL-CANCER ,PRECISION MEDICINE ,KINASE INHIBITORS ,TUMOR-GROWTH ,CETUXIMAB ,EVOLUTION ,AMPLIFICATION ,SENSITIVITY ,ACTIVATION ,Bioinformatics ,03 medical and health sciences ,In vivo ,Mice, Inbred NOD ,Antineoplastic Combined Chemotherapy Protocols ,Exome Sequencing ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Molecular Targeted Therapy ,Gene Expression Profiling ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Tumor Burden ,ErbB Receptors ,030104 developmental biology ,Oncology ,Ras Signaling Pathway ,Drug Resistance, Neoplasm ,Colonic Neoplasms ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Antibody ,medicine.drug - Abstract
Purpose: Patient-derived xenografts (“xenopatients”) of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures (“xenospheres”) was generated and characterized for response to targeted therapies. Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807–20. ©2017 AACR. See related commentary by Napolitano and Ciardiello, p. 727
- Published
- 2017
12. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors
- Author
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William M. Rideout, Andrea Bertotti, Carla Boccaccio, Francesco Sassi, Livio Trusolino, Elia Cipriano, Francesca Orzan, Timothy Perera, Francesca De Bacco, Elena Menietti, Gigliola Reato, Paolo M. Comoglio, May Han, Viola Bigatto, and Paolo Luraghi
- Subjects
Cancer Research ,Cell Survival ,Colorectal cancer ,medicine.medical_treatment ,Antineoplastic Agents ,Mice, Transgenic ,colorectal cancer ,Mice, SCID ,Pharmacology ,Antibodies, Monoclonal, Humanized ,medicine.disease_cause ,Targeted therapy ,resistance ,Mice ,Mice, Inbred NOD ,Spheroids, Cellular ,cetuximab ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,HGF ,Cell Proliferation ,EGFR inhibitors ,Cetuximab ,Hepatocyte Growth Factor ,business.industry ,Drug Synergism ,Proto-Oncogene Proteins c-met ,medicine.disease ,Xenograft Model Antitumor Assays ,invasive growth ,Tumor Burden ,ErbB Receptors ,Oncology ,Drug Resistance, Neoplasm ,Colonic Neoplasms ,Monoclonal ,Neoplastic Stem Cells ,Female ,Hepatocyte growth factor ,KRAS ,Signal transduction ,business ,Signal Transduction ,medicine.drug - Abstract
Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer–initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed “xenospheres,” were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts; like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, whereas those harboring wild-type RAS pathway genes (RASwt) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RASwt CCICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof-of-concept for concurrent targeting of these two pathways in the clinical setting. Cancer Res; 74(6); 1857–69. ©2014 AACR.
- Published
- 2014
13. Abstract B17: Xenospheres: a comprehensive patient-derived in vitro model to study response and resistance to targeted therapies in metastatic colorectal cancer
- Author
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Livio Trusolino, Elia Cipriano, Carla Boccaccio, Francesco Sassi, Gigliola Reato, Andrea Bertotti, Claudio Isella, Paolo M. Comoglio, Paolo Luraghi, and Viola Bigatto
- Subjects
Cancer Research ,Cetuximab ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,Cancer ,Lapatinib ,medicine.disease ,Targeted therapy ,Paracrine signalling ,Oncology ,Immunology ,medicine ,Cancer research ,ERBB3 ,Autocrine signalling ,business ,medicine.drug - Abstract
Although EGFR targeted therapy has improved the survival outcome of patients with metastatic colorectal cancer, lack of response or emergence of secondary resistance frequently occurs as result of genetic alterations that hyperactivate the RAS pathway or by activation of compensatory pathways by signals from the tumor microenvironmet that can also induce a stem-like phenotype. From patient-derived xenografts (“xenopatients”) of colorectal cancer liver metastases, we generated primary sphere cultures (“xenospheres”) that display the properties of cancer stem-like cells. Indeed, these cells can long-term self-propagate in vitro, and form phenocopies of original patient tumors in vivo (“spheropatients”), maintaining the same response to anti-EGFR therapy. We obtained a panel of xenospheres derived from more than 40 different xenopatients, all genetically characterized for the presence of mutations in genes that are predictive for response to EGFR targeted therapy. The panel included xenospheres harboring mutations in RAS genes (Rasmut), or recently identified rare predictors of resistance: ERBB2 amplification/mutation, MET amplification, EGFR mutation in the extracellular domain, and IGF2 overexpression. Moreover, we conducted an extensive exome-sequencing analysis of 10 xenospheres, for which the exome data of the matched xenopatients were available, thus allowing a complete and robust comparison. Xenospheres displayed a good genetic stability and a remarkable correspondence with xenopatients, in both the mutational and gene expression profiles. While RASmut xenospheres displayed self-sustained proliferative ability, those lacking mutations affecting the RAS pathway (RASwt) were strongly dependent of exogenous growth factors. We thus assessed the response of all RASwt xenospheres to ligands of the EGF family (TGFA, EREG, AREG, HB-EGF, NRG1), or bFGF, or HGF, testing both proliferation and response to EGFR inhibition (cetuximab). We found that TGFA and HB-EGF induced proliferation and resistance to cetuximab with almost the same potency of EGF, while EREG and AREG had a weak mitogenic activity and did not protect against cetuximab treatment, accordingly with observations in patients and xenopatients. The different proliferative activity (and protection against cetuximab) can be at least in part explained by the effect on receptor stabilization and exposure to the cell membrane exerted by different ligands. Interestingly, we found that, among all EGF family ligands, NRG1 (binding ERBB3/4) had the most potent mitogenic activity and protection against cetuximab treatment. NRG1 was able to replace EGF in sustaining xenosphere propagation, without altering the global gene expression profile, implying that it could sustain cancer-stem like cell properties similarly to EGF. To study the role of NRG1 in vivo we generated both an autocrine and a paracrine mode, by inducing its expression infecting either RASwt xenospheres or a cell line of murine fibroblasts. NRG1-expressing RASwt xenospheres became growth factor independent, resistant to cetuximab but sensitive to lapatinib (a dual EGFR/ERBB2 small molecule). Similar results were obtained using the conditioned medium of NRG1-expressing murine fibroblasts. By injecting parental and modified RASwt xenospheres into immunocompromised mice, we found that NRG1-expressing xenospheres had a strongly increased tumor onset, and that these tumors were resistant to cetuximab but sensitive to lapatinib treatment, suggesting its possible use in the clinical practice of RASwt patients. We conclude that xenospheres are a robust patient-derived in vitro model of colorectal cancer-stem like cells, amenable to study molecular mechanisms of response or resistance to targeted therapies. Citation Format: Paolo Luraghi, Viola Bigatto, Gigliola Reato, Elia Cipriano, Francesco Sassi, Claudio Isella, Andrea Bertotti, Livio Trusolino, Paolo Maria Comoglio, Carla Boccaccio. Xenospheres: a comprehensive patient-derived in vitro model to study response and resistance to targeted therapies in metastatic colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B17.
- Published
- 2016
14. 140: MET signaling in colorectal cancer-initiating cells blunts response to EGFR inhibition: Implications for targeted therapy
- Author
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Gigliola Reato, Elia Cipriano, Francesca Orzan, Carla Boccaccio, Elena Menietti, Francesco Sassi, Viola Bigatto, Andrea Bertotti, Livio Trusolino, and Paolo Luraghi
- Subjects
Cancer Research ,Oncology ,business.industry ,Colorectal cancer ,Egfr inhibition ,medicine.medical_treatment ,Cancer research ,Medicine ,business ,medicine.disease ,Targeted therapy - Published
- 2014
15. 759 Xenospheres – a Preclinical Model of Tumor-initiating Cells to Study the Response to Targeted Therapies in Metastatic Colorectal Cancer
- Author
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Gigliola Reato, Paolo M. Comoglio, Paolo Luraghi, Francesco Sassi, Elia Cipriano, Carla Boccaccio, Andrea Bertotti, Giorgia Migliardi, Livio Trusolino, and Elena Menietti
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Internal medicine ,Medicine ,business ,medicine.disease ,Tumor Initiating Cells - Published
- 2012
16. Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer
- Author
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Élia Cipriano and Alexandra Mesquita
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Metastatic triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis and currently with few treatment options. Treatment of these patients is highly based on systemic chemotherapy. Some targeted drugs were recently approved for these patients: two poly(ADP-ribose) polymerase inhibitors in patients with germline BRCA1/2 mutations (olaparib and talazoparib), immune checkpoint inhibitors in association with chemotherapy if programmed death-ligand 1 positive (atezolizumab plus nabpaclitaxel and pembrolizumab plus chemotherapy [nabpaclitaxel, paclitaxel, and carboplatin plus gemcitabine]), and an antibody-drug conjugate sacituzumab-govitecan in heavily pretreated patients (at least 2 previous lines for the metastatic setting). Combinations using these and other targeted treatment options are under investigation in early and late clinical trials, and we will probably have some practice-changing results in the new future. Other targeted drugs explored in phase II and phase III clinical trials are PI3K/AKT pathway inhibitors and androgen receptor antagonists in patients with alterations in these signaling pathways. The definition of molecular subtypes has been essential for the development of these treatment strategies. Soon, the treatment of metastatic TNBC could be based on personalized medicine using molecular testing for targeted drugs instead of only systemic chemotherapy. The authors present a review of emerging treatment options in metastatic TNBC, focusing on targeted drugs, including the recent data published in 2020.
- Published
- 2021
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