Marcello Gambacorta

Publications (8)22.5 Total impact

• Source

  Available from: Claudio Isella

  Article: A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.

  Andrea Bertotti, Giorgia Migliardi, Francesco Galimi, Francesco Sassi, Davide Torti, Claudio Isella, Davide Corà, Federica Di Nicolantonio, Michela Buscarino, Consalvo Petti, [......], Mauro Risio, Lorenzo Capussotti, Marcello Gambacorta, Salvatore Siena, Enzo Medico, Anna Sapino, Silvia Marsoni, Paolo M Comoglio, Alberto Bardelli, Livio Trusolino
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  ABSTRACT: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need. SIGNIFICANCE: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting.
  Cancer discovery. 11/2011; 1(6):508-23.
• Article: A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

  Andrea Bertotti, Giorgia Migliardi, Francesco Galimi, Francesco Sassi, Davide Torti, Claudio Isella, Davide Cora, Federica Di Nicolantonio, Michela Buscarino, Consalvo Petti, [......], Mauro Risio, Lorenzo Capussotti, Marcello Gambacorta, Salvatore Siena, Enzo Medico, Anna Sapino, Silvia Marsoni, Paolo M. Comoglio, Alberto Bardelli, Livio Trusolino
  [show abstract] [hide abstract]
  ABSTRACT: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples (“xenopatients”) to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype–response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need.
  Cancer Discovery. 11/2011; 1:508-523.
• Article: Medullocytoma and Glioneurocytoma: Related Tumors?: Authors' Reply

  Felice Giangaspero, Giovanna Cenacchi, Federico Roncaroli, Marcello Gambacorta, Antonio Allegranza
  American Journal of Surgical Pathology 04/1997; 21(5):615-616. · 4.35 Impact Factor
• Article: Patterns of integrin common chain β1 and collagen IV immunoreactivity in hepatocellular carcinoma. Correlations with tumour growth rate, grade and size

  Carlo Patriarca MD, Massimo Roncalli, Marcello Gambacorta, Marzia Cominotti, Guido Coggi, Giuseppe Viale, Carlo Patriarca
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  ABSTRACT: Thirty cases of hepatocellular carcinoma (HCC) were investigated immunocytochemically for expression of β1 integrin molecule and of collagen IV. Immunoreactivity was related to the tumour proliferation index, as detected by PCNA immunostaining, and to tumour size and grade. Membrane β1 integrin immunoreactivity was deteccted in the neoplasticc cells of all cases, though two different staining patterns were clearly recognized. In 14 cases, β1 integrin immunoreactivity was confined to the cell-stroma interface, showing the same polarized pattern as the non-neoplastic cell counterpart. This staining pattern was associated significantly (P 0.0001) with low PCNA labelling (i.e. less than 20 per cent of neoplastic cells showing nuclear immunostaining. Conversely, 16 cases showed non-polarized pericellular β1 integrin immunostaining. This staining pattern was significantly associated (P < 0.0001)) with high PCNA labelling (more than 20 per cent of immunoreactive cells) and with tumour size greater than 4 cm in diameter (P < 0.0001). β1 Integrin, collagen IV, and PCNA immunoreactivities, however, did not correlate with the histological grade. The data emphasize that neoplastic progression of HCCs may be correlated with an aberrant expression of adhesion molecules and with a disruption of the collagen IV complement of basal membranes.
  The Journal of Pathology 08/1993; 171(1):5 - 11. · 6.32 Impact Factor
• Article: Glial fibrillary acidic protein immunoreactivity in normal and diseased human breast

  Giuseppe Viale, Marcello Gambacorta, Guido Coggi, Patrizia Dell'Orto, Marina Milani, Claudio Doglioni
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  ABSTRACT: Immunostaining for glial fibrillary acidic protein (GFAP) identifies a minor subpopulation of immunoreactive myoepithelial cells in the normal resting human breast. The GFAP-immunoreactive cells also express a panel of myoepithelial cell markers, including cytokeratin 14 (CK 14), vimentin, smooth-muscle-specific actin isoforms, nerve growth factor receptor (NGFR) and common acute lymphoblastic leukaemia antigen (CALLA). The percentage of GFAP-immunoreactive myoepithelial cells is greatly increased in various neoplastic and non-neoplastic diseases of the breast, being highest in adenomyoepitheliomas. Furthermore, in all the instances of fibroadenoma, phyllodes tumour, epitheliosis and gynaecomastia, a variable number of epithelial cells also acquires immunoreactivity for GFAP, vimentin, CK 14, NGFR and, to a lesser extent, for CALLA. Conversely, GFAP immunoreactivity has never been encountered in the malignant cells of the different types of breast carcinoma. These findings suggest that the expression of GFAP might be a (possibly transient) feature of proliferating epithelial and myoepithelial cells in breast diseases other than carcinomas.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/1991; 418(4):339-348. · 2.49 Impact Factor
• Article: “Desmoplastic” versus “classic” medulloblastoma: Comparison of DNA content, histopathology and differentiation

  Felice Giangaspero, Pasquale Chieco, Claudio Ceccarelli, Gina Lisignoli, Roberto Pozzuoli, Marcello Gambacorta, Giorgio Rossi, Peter C. Burger
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  ABSTRACT: A microfluorometric analysis was performed to analyse the DNA content of 42 medulloblastomas (MBs) and to seek correlations, if any existed, between the DNA distribution and ploidy values, neoplasm types (i.e. classic vs desmoplastic), histological features of aggressiveness, and immunocytochemical features indicating glial and/or neuronal differentiation. Thirty-one cases were classified as classic and 11 cases as desmoplastic MBs. Ten of 11 desmoplastic MBs had a near-diploid main mode and the remaining 1 case had a near-tetraploid main mode. Moreover, 10 of 11 (90%) cases showed a monomodal DNA distribution diagram. All these cases showed a uniform histology. In contrast, classic MBs represented a heterogeneous group of neoplasms. Twenty-two cases were near-diploid, 5 cases were near-tetraploid and 3 cases were near-triploid. The histogram type distribution showed a similar heterogeneity. Twelve of 31 (39%) cases had a monomodal histogram, 12 (39%) cases had a bimodal diagram and 7 (22%) cases a complex DNA distribution. There was a statistically significant difference (P
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/1991; 418(3):207-214. · 2.49 Impact Factor
• Article: Lack of Diagnostic Utility of Vimentin Immunostaining

  Giuseppe Viale, Patrizia Dell'Orto, Guido Coggi, Marcello Gambacorta
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  ABSTRACT: We documented the coexpression of cytokeratins and vimentin in epithelial cells of the thyroid gland in 100 samples examined from 65 patients. These included normal, inflammatory, and neoplastic tissues that were routinely fixed in formalin and embedded in paraffin. The number of epithelial cells coexpressing the two intermediate filament proteins as well as the subcellular compartmentalization of vimentin immunoreactivity did not correlate with the various conditions of the thyroid gland. Therefore, we conclude that the immunolocalization of vimentin does not represent a useful adjunct tool for the histopathological diagnosis of thyroid diseases. (C) Lippincott-Raven Publishers.
  American Journal of Surgical Pathology 11/1989; 13(12). · 4.35 Impact Factor
• Article: Coexpression of cytokeratins and vimentin in common epithelial tumours of the ovary: An immunocytochemical study of eighty-three cases

  Giuseppe Viale, Marcello Gambacorta, Patrizia Dell'Orto, Guido Coggi
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  ABSTRACT: An immunocytochemical investigation has been performed on 83 common epithelial tumours of the ovary, to ascertain their capability of expressing vimentin in addition to cytokeratins. Our results demonstrate that vimentin coexpression is related to the tumour histotype and -to a lesser extent- to the degree of differentiation of malignant variants. Indeed, most serous tumours (80%), some endometrioid adenocarcinomas, and all the clear cell carcinomas investigated exhibited a variable number of neoplastic cells co-synthesizing the two distinct intermediate filament (IF) proteins, whereas only one of 29 mucinous tumours and none of the Brenner tumours displayed vimentin-immunoreactive cells. Moreover, in serous and endometrioid carcinomas, the expression of vimentin was related to the degree of tumour differentiation, being consistently identifiable in the better differentiated cases. The immunocytochemical findings of a parallel investigation on IF expression in the ovarian coelomic epithelium and in the mllerian-derived epithelia of the female genital tract allowed us to ascertain that ovarian epithelial tumours (with the possible exception of poorly differentiated carcinomas) maintain the pattern of IF expression typical of the normal epithelia. This investigation emphasizes the usefulness of IF typing as a tool for the more precise characterization of the origin and differentiation of human neoplasms.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/1988; 413(2):91-101. · 2.49 Impact Factor