Dott. Antonio D'Ambrosio

f502-c003 Dottorato in Medicina Molecolare
Dottorato: 29° ciclo
Matricola: 74760

Contatti

011-9933220/3205
074760@studenti.unito.it
Cancer Stem Cell laboratory - Candiolo Cancer Institute ¶? IRCCS -University of
Torino (Turin), Dept. of Oncology, Str. Prov. 142, 10060 Candiolo (TO)-Italy
https://dott-mm.campusnet.unito.it/do/studenti.pl/Show?74760
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Supervisore

Tesi di dottorato

“Overcoming Cancer Stem Cells radioresistance by MET inhibition”

Background: Radiation therapy is a widely employed and effective tumor treatment, but its success is limited by radioresistance. In Glioblastoma (GBM), radioresistance has been associated with the findings that ionizing radiations (IR) destroy the tumor bulk, but not Glioblastoma Stem Cells (GSCs), which are endowed with increased ability to repair radiation-induced damage and drive tumor recurrence. We recently showed that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We also found that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in xenografts generated by GSCs transplantation. Interestingly, MET expression was recently found to be a predictive marker of poor response to the neoadjuvant radiotherapy, administered before surgical resection to locally advanced rectal carcinoma. Although colon CSCs have been widely described, limited information is available on CSCs derived from rectal cancer. Further investigation is needed to elucidate their response to conventional radiotherapy and the possible involvement of MET in their radioresistance.

Scientific goal: We showed that MET mediates GBM stem cell radioresistance and that MET inhibition radiosensitizes GBM by depletion of its stem cell component. Based on these findings, our aim is to investigate whether MET can confer radioresistance to rectal CSCs, and whether it could be exploited as a therapeutic target to radiosensitize rectal carcinoma, possibly at stem cell level.

Methods applied: MET-positive-neurospheres (in vitro cultures enriched in stem and progenitor cells), isolated from primary human GBM were implanted either subcutaneously and intracranially in NOD-SCID mice. Following randomization, xenografts underwent targeted irradiation by Helical Tomotherapy HD (fractionated dose of 2Gy × 3 consecutive days) and, concomitantly, mice were treated by daily oral administration of the MET inhibitor JNJ-38877605. In orthotopic models, tumor growth was monitored and quantified using bioluminescent or epifluorescent GFP-signal (IVIS-Spectrum CT System). To assess glioblastoma stem cell frequency, in vitro and in vivo Limiting Dilution Assay was performed. Rectospheres were obtained both from human rectal carcinoma samples or from patient-derived xenografts (PDXs) obtained by transplanting patient rectal tumor specimens in NOD-SCID mice. Rectal spheres were genetically and phenotypically characterized. MET expression was assessed on a large panel of human rectal cancer by immunohistochemistry (IHC).

Results: In GBM, we showed that association of the MET inhibitor JNJ-33877605 with therapeutic doses of IR significantly enhanced the efficacy of radiotherapy, leading in some cases to regression of subcutaneous tumor xenografts. Consistently, the survival of mice treated with both radiotherapy and the MET inhibitor was significantly prolonged compared with either treatment alone. In orthotopic xenografts, we assessed that JNJ-33877605 crosses the blood-brain barrier and that combination therapy dramatically reduced tumor growth. Importantly, the combination treatment led to decreased glioblastoma stem cell frequency in vitro and in vivo as measured by Limiting Dilution Assay. In rectal carcinoma, MET expression was assessed on a large panel of human samples, both naïve or irradiated before surgery. MET expressing rectal samples were transplanted to generate PDXs. From PDXs four different rectospheres were isolated: genetic and phenotypic characterization and functional analysis to investigate the role of MET in rectal stem cell radioresistance are ongoing.

Conclusions and perspectives: Our findings indicate that targeting the MET oncogene significantly contributes to radiosensitize GBM, by depleting its stem cell compartment. Studies are ongoing to assess whether MET inhibition can be exploited to radiosensitize other tumors such as rectal cancer, by depleting their cancer stem cell component. In vitro and in vivo models will be established to provide robust preclinical data.

Attività di ricerca

- Targeting the MET oncogene to overcome rectal cancer stem cell radioresistance;

- Targeting the MET oncogene to overcome glioblastoma stem cell radioresistance;

- Isolation and characterization of intratumor heterogeneous glioblastoma stem cell subclones;

- Isolation and characterization of Cancer Stem Cells from Cancer of Unknown Primary site.

A. Miranti, A. D’Ambrosio, G. Cattari, E. Garibaldi, S. Bresciani, P. Gabriele, M. Stasi. “NOD-SCID mice irradiation with Tomotherapy and TrueBeam STx: dosimetric and radiobiological results” Physica Medica: European Journal of Medical Physics (2016) – under revision;

De Bacco F, D’Ambrosio A, Casanova E, Orzan F, Neggia R, Albano R, Verginelli F, Cominelli M, Poliani PL, Luraghi P, Reato G, Pellegatta S, Finocchiaro G, Perera T, Garibaldi E, Gabriele P, Comoglio PM, Boccaccio C. “MET inhibition overcomes radiation resistance of glioblastoma stem-like cells” EMBO Molecular Medicine (2016) 2;8 (5): 550-68;

De Bacco F, Casanova E, Medico E, Pellegatta S, Orzan F, Albano R, Luraghi P, Reato G, D'Ambrosio A, Porrati P, Patane M, Maderna E, Pollo B, Comoglio PM, Finocchiaro G, Boccaccio C. “The MET oncogene is a functional marker of a glioblastoma stem cell subtype” Cancer Research (2012) 72(17): 4537-50.

Progress Report, 20/1/2015 - Targeting the MET oncongene to overcome glioblastoma stem cell radioresistance - Candiolo Cancer Institute - IRCCS

Progress Report, 13/12/2016 - Overcoming cancer stem cell radioresistance by MET inhibition - Candiolo Cancer Institute - IRCCS

2016:

- Cancer Stem Cells (CSC): Impact on Treatment – 7-11 December 2016, Obergulg (Austria)- Abstract and poster:“MET inhibition overcomes radiation resistance of glioblastoma stem-like cells”De Bacco Francesca, D'Ambrosio Antonio, Casanova Elena, Orzan Francesca, Neggia Roberta, Albano Raffaella, Verginelli Federica, Cominelli Manuela, Poliani Pietro L., Luraghi Paolo, Reato Gigliola, Pellegatta Serena, Finocchiaro Gaetano, Perera Timothy, Garibaldi Elisabetta, Gabriele Pietro, Comoglio Paolo M., Boccaccio Carla.

- ESMO 2016 – 7-11 October 2016, Copenhagen (Denmark) -Abstract and poster:“AGNOSTOS precision medicine project in patients with Cancer of Unknown Primary (CUP)”E. Geuna, S. Benvenuti, F. Verginelli, D. Galizia, S. Siena, G. Stella, A. Gentile, M. Milan, A. Virzì, A. D’Ambrosio, P. Cassoni, R. Senetta, A. Balsamo, M. Spione, A. Nuzzo, A. Sapino, S. Marsoni, C. Boccaccio, P.M. Comoglio, F. Montemurro.

- 58th Annual Meeting of the Italian Cancer Society – 5-8 September 2016, Verona (Italy) – Abstract and poster:“MET inhibition overcomes radiation resistance of glioblastoma stem-like cells”Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Francesca Orzan, Roberta Neggia, Raffaella Albano, Federica Verginelli, Manuela Cominelli, Pietro L. Poliani, Paolo Luraghi, Gigliola Reato, Serena Pellegatta, Gaetano Finocchiaro, Timothy Perera, Elisabetta Garibaldi, Pietro Gabriele, Paolo M.Comoglio and Carla Boccaccio.

- ESTRO 35 CONGRESS – 29 april-3 may 2016, Torino (Italy) – Abstract and poster:“Small animal irradiation by using tomotherapy: dosimetric and preclinical results”Miranti A, D'Ambrosio A, Cattari G, Garibaldi E, Bresciani S, Gabriele P, Stasi M.

- AIFM – 25-28 february 2016, Perugia (Italy) – Abstract:“ Dosimetric and preclinical results of small animal irradiation by using tomotherapy”A. Miranti, A. D'Ambrosio, G. Cattari, S. Bresciani, M. Poli, C. Cutaia, P. Gabriele, M. Stasi.

2015:

- GBM 2015 - II International Symposium on Clinical and Basic Investigation in Glioblastoma - 9- 12 september 2015, Toledo (Spain) – Abstract and poster: "MET inhibition overcomes radiation resistance of glioblastoma stem-like cells" Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Roberta Neggia, Raffaella Albano, Francesca Orzan, Federica Verginelli, Gigliola Reato, Paolo Luraghi, Serena Pellegatta, Gaetano Finocchiaro, Elisabetta Garibaldi, Pietro Gabriele, Paolo M. Comoglio and Carla Boccaccio.

- CYTO 2015-XXX Congress of the International Society for Advancement of Cytometry – 26-30 june 2015, Glasgow (UK) – Abstract and poster: “The low-affinity neurotrophin receptor p75 identifies cell line subpopulations displaying stem-like properties in vitro and increased tumorigenicity in vivo” Casanova E. § , De Bacco F.§ , Angelini P., Geuna M., Neggia R., D’Ambrosio A., Reato G., Luraghi P., Pisacane A., Comoglio P.M., Boccaccio C.

- ISSCR 2015, 24-27 june 2015, Stockholm (Sweden) – Abstract and poster: “Targeting the MET oncogene overcomes Glioblastoma Stem-like Cell radioresistance” Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Roberta Neggia, Raffaella Albano, Francesca Orzan, Federica Verginelli, Gigliola Reato, Paolo Luraghi, Serena Pellegatta, Gaetano Finocchiaro, Elisabetta Garibaldi, Pietro Gabriele, Paolo M. Comoglio and Carla Boccaccio.

- EACR-AACR-SIC Special Conference on Anticancer Drug Action and Drug Resistance: from Cancer Biology to the Clinic – 20-23 june 2015, Firenze (Italy) – Abstract and poster: “Targeting the MET oncogene overcomes Glioblastoma Stem-like Cell radioresistance” Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Roberta Neggia, Raffaella Albano, Francesca Orzan, Federica Verginelli, Gigliola Reato, Paolo Luraghi, Serena Pellegatta, Gaetano Finocchiaro, Elisabetta Garibaldi, Pietro Gabriele, Paolo M. Comoglio and Carla Boccaccio.

- IRCCS International Conference - Molecular Oncology From Signal Transduction to Cancer Precision Medicine' – 6-7 june 2015, Candiolo (Italy) – Abstract and poster: “MET inhibitions impairs radiation resistance of glioblastoma stem-like cells ” Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Roberta Neggia, Raffaella Albano, Francesca Orzan, Federica Verginelli, Gigliola Reato, Paolo Luraghi, Serena Pellegatta, Gaetano Finocchiaro, Elisabetta Garibaldi, Pietro Gabriele, Paolo M. Comoglio and Carla Boccaccio.

2014:

- IRCCS Candiolo Cancer Institute – MCO 2014 - October 4-5 2014, Torino (Italy) - Abstract and poster: “Irradiation of preclinical models: proposal of a new technique” Elisabetta Garibaldi, Gabriella Cattari, Anna Miranti, Claudia Cutaia, Antonio D’Ambrosio, Francesca De Bacco, Carla Boccaccio and Pietro Gabriele.

- IRCCS Candiolo Cancer Institute – MCO 2014- October 4-5 2014, Torino (Italy) - Abstract and poster: “MET signaling sustains Glioblastoma Stem-like Cells radioresistance” Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Francesca Orzan, Raffaella Albano, Serena Pellegatta, Roberta Neggia, Gigliola Reato, Gaetano Finocchiaro, Paolo M. Comoglio and Carla Boccaccio.

- EACR23, July 5-8 2014 – Munich (Germany) - Abstract and poster: “MET signaling sustains Glioblastoma Stem-like Cells radioresistance” Francesca De Bacco, Antonio D’Ambrosio, Elena Casanova, Francesca Orzan, Raffaella Albano, Serena Pellegatta, Roberta Neggia, Gigliola Reato, Gaetano Finocchiaro, Paolo M. Comoglio and Carla Boccaccio.

2013:

– GIC XXXI Cytometry National Conference “La Citometria dalla ricerca alla clinica” - October 8-11 2013, Lucca (Italy) -Abstract and poster: "The MET Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype" De Bacco F., Casanova E., Medico E., Pellegatta S.,Orzan F., Albano R., D’Ambrosio A., Pollo B., Comoglio P.M., Finocchiaro G., Boccaccio C.

- ISCRR 11th annual meeting - June 12-15 2013 - Boston, MA (USA) - Abstract and poster: “The MET oncogene is a functional marker of a glioblastoma stem cell subtype and a therapeutical target for radiosensitization” Boccaccio Carla, De Bacco Francesca, Casanova Elena, Medico Enzo, Pellegatta Serena,Orzan Francesca, Albano Raffaella, Luraghi Paolo, D'Ambrosio Antonio, Pollo Bianca, Comoglio Paolo M.,Finocchiaro Gaetano.

– ESTRO (European Society for Radiotherapy and Oncology) Forum - April 19-23 2013, Geneva (Switzerland) - Abstract and poster: "Targeting the MET oncogene to radiosensitize cancer stem cells" Boccaccio C., De Bacco F., Casanova E., Orzan F., D’Ambrosio A., Gabriele P., Pellegatta S., Finocchiaro G., Comoglio P.M.

2012:

– EACR 22^nd Congress - July 7-10 2012, Barcelona (Spain) - Abstract and poster: "Tyrosine Kinase Receptors as Functional Markers and Therapeutical Targets of Glioblastoma Stem Cells" De Bacco F., Casanova E., Medico E., Pellegatta S., Orzan F., Albano R., D’Ambrosio A., Pollo B., Finocchiaro G., Boccaccio C.

2016:

3rd Symposium on Small Animal Precision Image-Guided Radiotherapy -21-23 March 2016, Ghent (Belgium);

2015:

GINP -IL GLIOBLASTOMA. RIUNIONE DEL GRUPPO ITALIANO DI NEUROPATOLOGIA (GINP) - November 20 2015 - A.O. Spedali Civili di Brescia, Brescia (Italy);

ESMO MAP 2015 – Molecular Analysis for personalized therapy – 23-24 October 2015, Paris (France);

GBM 2015 - II International Symposium on Clinical and Basic Investigation in Glioblastoma - 9- 12 september 2015, Toledo (Spain);

ISSCR 2015, 24-27 june 2015, Stockholm (Sweden);

IRCCS International Conference - Molecular Oncology From Signal Transduction to Cancer Precision Medicine' – 6-7 june 2015, Candiolo (Italy).

2014:

EMBO – Cancer stem cells 20 years later: Achievements, controversies, emerging concepts and technologies - October 3-6 2014, Catanzaro (Italy).

2011:

IRCC International Conference “Molecular Clinical Oncology” - May 26-28 2011, Torino (Italy).

2016:

Participation to weekly internal progress reports at Candiolo Cancer Institute – IRCCS -University of Torino, Dept. of Oncology; (http://www.ircc.it/irccit/?q=progress);

October 21, 2016 – “Mechanisms regulating tumor heterogeneity” – Candiolo Cancer Institute - IRCCS
Prof. Cedric Blanpain;

September 19, 2016 – “Neutral evolution in cancer: distinguishing functional from nonfunctional intra-tumour heterogeneity” – Candiolo Cancer Institute - IRCCS
Dr. Andrea Sottoriva;

September 12, 2016- “Intra-tumoural heterogeneity and stratified medicine; perfect partners or mortal enemies?”- Candiolo Cancer Institute - IRCCS
Dr. Philip Dunne;

September 8, 2016 – “The Fluidigm C1 platform for single cell analysis” - Candiolo Cancer Institute – IRCCS
Amy Hamilton;

May 27, 2016 – “Control of cell identity by polycomb group proteins”- Candiolo Cancer Institute – IRCCS
Prof. Davide Pasini;

May 11, 2016 – “Advanced Flow Cytometry Day” - Candiolo Cancer Institute – IRCCS
Miltenyi Biotec

April 29, 2016 – “AIRC Support to Cancer Research: Strategies and Perspectives” - Candiolo Cancer Institute – IRCCS
Prof. Federico Caligaris-Cappio;

March 25, 2016 – “Breast Cancer stem Cells targeting: a new step for intratumoral heterogeneity in the light of personalized medicine” - Candiolo Cancer Institute – IRCCS
Prof. Emmanuelle Charafe Jauffret;

March 22, 2016 – “The transparent editorial process, data reproducibility and research integrity at EMBO”- Candiolo Cancer Institute – IRCCS
Dr. Roberto Buccione, Ph.D;

March 9, 2016 – “A Systems Approach to Drug Discovery: Blocking EGFR Inhibitor Resistance in Colorectal Cancer” - Candiolo Cancer Institute – IRCCS
Dr. Gavin Mac Beath;

February 12, 2016- “Immunotherapy, microbiota and cancer”- Candiolo Cancer Institute – IRCCS
Maria Rescigno;

January 28, 2016 – “TAK-ing aim at Treatment Resistance in Gastrointestinal Tumors”- Candiolo Cancer Institute – IRCCS
Prof. Davide Melisi;

2015:

December 11, 2015 – “Regulation of self renewal in Cancer Stem Cells” - Candiolo Cancer Institute – IRCCS
Prof. Pier Giuseppe Pelicci;

November 9, 2015 – “NanoBiT Complementation Reporter Provides Accurate Assessment of Intracellular Protein Interactions under Physiological Conditions” - Candiolo Cancer Institute – IRCCS Keith V. Wood, PhD;

October 2, 2015 – “Therapeutic strategies based on cancer stem cell targeting” - Candiolo Cancer Institute – IRCCS Prof. Ruggero De Maria; May 4, 2015 – “Tumor clonal expansion and impact on treatment selection” - Candiolo Cancer Institute – IRCCS Prof. Francesca Ciccarelli;

March 20, 2015 – “Neuropilin and Integrin Control of Cancer Stem Cell Fate” - Candiolo Cancer Institute – IRCCS Dr. Arthur M.Mercurio;

January 26, 2015 – “Colon cancer stem cell resistance to therapy” - Candiolo Cancer Institute – IRCCS Dr. Jan Paul Medema;

January 26, 2015 – “Tumor heterogeneity in colon cancer: therapeutic implications” - Candiolo Cancer Institute – IRCCS Dr. Nicola Normanno.

October 11, 2012 -Must most metastatic cancer remain "incurable" ? - Candiolo Cancer Institute - IRCCS James Dewey Watson, Nobel Prize Cold Spring Harbor Laboratory - USA.

May 9, 2011 - "Roles of telomeres and telomerase in cancer" - Candiolo Cancer Institute - IRCCS Professor Elisabeth Blackburn, Nobel Prize University of California at San Francisco - USA.