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7. Development of a Multiomics Database for Personalized Prognostic Forecasting in Head and Neck Cancer: The Big Data to Decide EU Project

Author

Cavalieri, Stefano, Cecco, L. de, Brakenhoff, R.H., Serafini, M.S., Canevari, S., Rossi, S., Lanfranco, D., Hoebers, F.J.P., Wesseling, F.W.R., Keek, S., Scheckenbach, K., Mattavelli, D., Hoffmann, T., López Pérez, L., Fico, G., Bologna, M., Nauta, I., Leemans, C.R., Trama, A., Klausch, T., Berkhof, J.H., Tountopoulos, V., Shefi, R., Mainardi, L., Mercalli, F., Poli, T., Licitra, L., Wesarg, S., and Publica

Subjects
Lead Topic: Individual Health, Research Line: Modeling (MOD), Research Line: Machine Learning (ML), Big Data, patient model, oral cancer
Abstract

Background Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling. Methods Stage III-IV HNSCC patients with locoregionally advanced HNSCC treated with curative intent (1537) were included. Whole transcriptomics and radiomics analyses were performed using pretreatment tumor samples and computed tomography/magnetic resonance imaging scans, respectively. Results The entire cohort was composed of 71% male (1097)and 29% female (440): oral cavity (429, 28%), oropharynx (624, 41%), larynx (314, 20%), and hypopharynx (170, 11%); median follow-up 50.5 months. Transcriptomics and imaging data were available for 1284 (83%) and 1239 (80%) cases, respectively; 1047 (68%) patients shared both. Conclusions This annotated database represents the HNSCC largest available repository and will enable to develop/validate a decision support system integrating multiscale data to explore through classical and machine learning models their prognostic role.

Published
2021

9. An immunologically relevant rodent model demonstrates safety of therapy using a tumour‐specific IgE

Author

Josephs, D. H., Nakamura, M., Bax, H. J., Dodev, T. S., Muirhead, G., Saul, L., Karagiannis, P., Ilieva, K. M., Crescioli, S., Gazinska, P., Woodman, N., Lombardelli, C., Kareemaghay, S., Selkirk, C., Lentfer, H., Barton, C., Canevari, S., Figini, M., Downes, N., Dombrowicz, D., Corrigan, C. J., Nestle, F. O., Jones, P. S., Gould, H. J., Blower, P. J., Tsoka, S., Spicer, J. F., and Karagiannis, S. N.

Subjects
AllergoOncology, Receptors, IgE, Tumor Necrosis Factor-alpha, Immunoglobulin E, Statistics, Nonparametric, Rats, Antibodies, Monoclonal, Murine-Derived, Mice, Treatment Outcome, Experimental Allergy and Immunology, Cell Line, Tumor, Immunoglobulin G, Neoplasms, Models, Animal, cancer, Animals, Humans, Original Article, rat, Folate Receptor 1, IgE, Immunotherapy, ORIGINAL ARTICLES, Protein Binding
Abstract

Background Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class‐specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. Methods We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour‐associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE‐FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. Results In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a “cytokine storm” or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE‐mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour‐bearing lungs. Conclusion Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

Published
2018

13. Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcεRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity

Author

Rudman, S. M., Josephs, D. H., Cambrook, H., Karagiannis, P., Gilbert, A. E., Dodev, T., Hunt, J., Koers, A., Montes, A., Taams, L., Canevari, S., Figini, M., Blower, P. J., Beavil, A. J., Nicodemus, C. F., Corrigan, C., Kaye, S. B., Nestle, F. O., Gould, H. J., Spicer, J. F., and Karagiannis, S. N.

Published
2011
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17. Isometric immersions of space forms into Sp×R.

Author

Canevari, S. and Tojeiro, Ruy

Subjects
*RIEMANNIAN manifolds, *SPACE, *CURVATURE
Abstract

In this article we classify isometric immersions f:Mn(c)→Sn+p×R of Riemannian manifolds of dimension n and constant sectional curvature c≤1 into the product space Sn+p×R, p≤n−3, where Sm denotes the m‐dimensional unit sphere. [ABSTRACT FROM AUTHOR]

Published
2020
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21. Late abstracts 186–187

Author

Jaehne, J., Meyer, H. -J., Wittekind, Ch., Maschek, H., Pichlmayr, R., Jacobi, G., Weiermann, G., Vitzthum, H. Gräfin, Schwabe, D., Manegold, Ch., Krempien, B., Kaufmann, M., Bailly, M., Doré, J. -F., Fodstad, Ø., Kjønniksen, I., Brøgger, A., Flørenes, V. A., Pihl, A., Aamdal, S., Nesland, J. M., Geldof, A. A., Rao, B. R., De Giovanni, C., Lollini, P. -L., Del Re, B., Scotlandi, K., Nicoletti, G., Nanni, P., Van Muijen, G. N. P., Van Der Wiel-Miezenbeek, J. M., Cornelissen, L. M. H. A., Jansen, C. F. J., Ruiter, D. J., Kieler, J., Oda, Y., Tokuriki, Y., Tenang, E. M., Lamb, J. F., Galante, E., Zanoni, F., Galluzzi, D., Cerrotta, A., Martelli, G., Guzzon, A., Reduzzi, D., Barberá-Guillem, E., Barceló, J. R., Urcelay, B., Alonso-Varona, A. I., Vidal-Vanaclocha, F., Bassukas, I. D., Maurer-Schultze, B., Storeng, R., Manzotti, C., Pratesi, G., Schachert, G., Fidler, I. J., Grimstad, I. A., Rutt, G. Th., Riesinger, P., Frank, J., Neumann, G., Wissler, J. H., Bastert, G., Liebrich, W., Lehner, B., Gonzer, S., Schlag, P., Vehmeyer, K., Hajto, T., Gabius, H. -J., Funke, I., Schlimok, G., Bock, B., Dreps, A., Schweiberer, B., Riethmüller, G., Nicolai, U., Vykoupil, K. -F., Wolf, M., Havemann, K., Georgii, A., Bertrand, S., N'Guyen, M. -J., Siracky, J., Kysela, B., Siracka, E., Pflüger, E., Schirrmacher, V., Boyano, M. D., Hanania, N., Poupon, M. F., Sherbet, G. V., Lakshmi, M. S., Van Roy, F., Vleminckx, K., Fiers, W., Dragonetti, C., De Bruyne, G., Messiaen, L., Mareel, M., Kuhn, S., Choritz, H., Schmid, U., Bihl, H., Griesbach, A., Matzku, S., Eccles, S. A., Purvies, H. P., Miller, F. R., McEachern, D., Ponton, A., Waghorne, C., Coulombe, B., Kerbel, R. S., Breitman, M., Skup, D., Gingras, M. C., Jarolim, L., Wright, J. A., Greenberg, A. H., N'Guyen, M. J., Allavena, G., Melchiori, A., Aresu, O., Percario, M., Parodi, S., Schmidt, J., Kars, P., Chader, G., Albini, A., Zöller, M., Lissitzky, J. C., Bouzon, M., Martin, P. M., Grossi, I. M., Taylor, J. D., Honn, K. V., Koch, B., Baum, W., Giedl, J., Gabius, H. J., Kalden, J. R., Hakim, A. A., LadÁnyi, A., Timár, J., Moczar, E., Lapis, K., Müller, K., Wolf, M. F., Benz, B., Schumacher, K., Kemmner, W., Morgenthaler, J., Brossmer, R., Hagmar, B., Burns, G., Erkell§, L. J., Ryd, W., Paku, S., Rot, A., Hilario, E., Unda, F., Simón, J., Aliño, S. F., Sargent, N. S. E., Burger, M. M., Altevogt, P., Kowitz, A., Chopra, H., Bandlow, G., Nagel, G. A., Lotan, R., Carralero, D., Lotan, D., Raz, A., Skubitz, A. P. N., Koliakos, G. G., Furcht, L. T., Charonis, A. S., Hamann, A., Jablonski-Westrich, D., Jonas, P., Harder, R., Butcher, E. C., Thiele, H. G., Breillout, F., Antoine, E., Lascaux, V., Boxberger, H. -J., Paweletz, N., Bracke, M., Vyncke, B., Opdenakker, G., Castronovo, V., Foidart, J. -M., Camacho, M., Fras, A. Fabra, Llorens, A., Rutllant, M. L., Erkell, L. J., Brunner, G., Heredia, A., Imhoff, J. M., Burtin, P., Nakajima, M., Lunec, J., Parker, C., Fennelly, J. A., Smith, K., Roossien, F. F., La Rivière, G., Roos, E., Erdel, M., Trefz, G., Spiess, E., Ebert, W., Verhaegen, S., Remels, L., Verschueren, H., Dekegel, D., De Baetselier, P., Van Hecke, D., Hannecart-Pokorni, E., Falkvoll, K. H., Alonso, A., Baroja, A., Sebbag, U., Barbera-Guillem, E., Behrens, J., Mareel, M. M., Birchmeier, W., Waterhouse, P., Khokha, R., Chambers, A., Yagel, S., Lala, P. K., Denhardt, D. T., Hennes, R., Frantzen, F., Keller, R., Schwartz-Albiez, R., Fondaneche, M. C., Mignatti, P., Tsuboi, R., Robbins, E., Rifkin, D. B., Overall, C. M., Sacchi, A., Falcioni, R., Piaggio, G., Rizzo, M. G., Perrotti, N., Kennel, S. J., Girschick, H., Müller-Hermelink, H. K., Vollmers, H. P., Wenzel, A., Liu, S., Günthert, U., Wesch, V., Giles, M., Ponta, H., Herrlich, P., Stade, B., Hupke, U., Holzmann, B., Johnson, J. P., Sauer, A., Roller, E., Klumpp, B., Güttler, N., Lison, A., Walk, A., Redini, F., Moczar, M., Leoni, F., Da Dalt, M. G., Ménard, S., Canevari, S., Miotti, S., Tagliabue, E., Colnaghi, M. I., Ostmeier, H., Suter, L., Possati, L., Rosciani, C., Recanatini, E., Beatrici, V., Diambrini, M., Polito, M., Rothbächer, U., Eisenbach, L., Plaksin, D., Gelber, C., Kushtai, G., Gubbay, J., Feldman, M., Benke, R., Benedetto, A., Elia, G., Sala, A., Belardelli, F., Lehmann, J. M., Ladanyi, A., Hanisch, F. -G., Sölter, J., Jansen, V., Böhmer, G., Peter-Katalinic, J., Uhlenbruck, G., O'Connor, R., Müller, J., Kirchner, T., Bover, B., Tucker, G., Valles, A. M., Gavrilovic, J., Thiery, J. P., Kaufmann, A. M., Volm, M., Edel, G., Zühlsdorf, M., Voss, H., Wörmann, B., Hiddemann, W., De Neve, W., Van Den Berge, D., Van Loon, R., Storme, G., Zacharski, L. R., Wojtukiewicz, M. Z., Memoli, V., Kisiel, W., Kudryk, B. J., Stump, D., Piñol, G., Gonzalez-Garrigues, M., Fabra, A., Marti, F., Rueda, F., Lichtner, R. B., Khazaie, K., Timar, J., Greenzhevskaya, S. N., Shmalko, Yu. P., Hill, S. E., Rees, R. C., MacNeil, S., Millon, R., Muller, D., Eber, M., Abecassis, J., Betzler, M., Bahtsky, K. P., Umansky, V. Yu., Krivorotov, A. A., Balitskaya, E. K., Pridatko, O. E., Smelkova, M. I., Smirnov, I. M., Korczak, B., Fisher, C., Thody, A. J., Young, S. D., Hill, R. P., Frixen, U., Gopas, J., Segal, S., Hammerling, G., Bar-Eli, M., Rager-Zisman, B., Har-Vardi, I., Alon, Y., Hämmerling, G. J., Perez, M., Algarra, I., Collado, Ma. D., Peran, E., Caballero, A., Garrido, F., Turner, G. A., Blackmore, M., Stern, P. L., Thompson, S., Levin, I., Kuperman, O., Eyal, A., Kaneti, J., Notter, M., Knuth, A., Martin, M., Chauffert, B., Caignard, A., Hammann, A., Martin, F., Dearden, M. T., Pelletier, H., Dransfield, I., Jacob, G., Rogers, K., Pérez-Yarza, G., Cañavate, M. L., Lucas, R., Bouwens, L., Mantovani, G., Serri, F. G., Macciò, A., Zucca, M. V., Del Giacco, G. S., Pérez, M., Kärre, K., Apt, D., Traversari, C., Sensi, M., Carbone, G., Parmiani, G., Hainaut, P., Weynants, P., Degiovanni, G., Boon, T., Marquardt, P., Stulle, K., Wölfel, T., Herin, M., Van den Eynde, B., Klehmann, E., Büschenfelde, K. -H. Meyer zum, Samija, M., Gerenčer, M., Eljuga, D., Bašić, I., Heacock, C. S., Blake, A. M., D'Aleo, C. J., Alvarez, V. L., Gresser, I., Maury, C., Moss, J., Woodrow, D., von Ardenne, M., Krüger, W., Möller, P., Schachert, H. K., Itaya, T., Frost, P., Rodolfo, M., Salvi, C., Bassi, C., Huland, E., Huland, H., Sersa, G., Willingham, V., Hunter, N., Milas, L., Schild, H., von Hoegen, P., Mentges, B., Bätz, W., Suzuki, N., Mizukoshi, T., Sava, G., Ceschia, V., Zabucchi, G., Farkas-Himsley, H., Schaal, O., Klenner, T., Keppler, B., Alvarez-Diaz, A., Bizzari, J. P., Barbera-Guillem, F., Osterloh, B., Bartkowski, R., LÖhrke, H., Schwahn, E., Schafmayer, A., Goerttler, K., Cillo, C., Ling, V., Giavazzi, R., Vecchi, A., Luini, W., Garofalo, A., Iwakawa, M., Arundel, C., Tofilon, P., Giraldi, T., Perissin, L., Zorzet, S., Piccini, P., Pacor, S., Rapozzi, V., Fink, U., Zeuner, H., Dancygier, H., Classen, M., Lersch, C., Reuter, M., Hammer, C., Brendel, W., Mathé, G., Bourut, C., Chenu, E., Kidani, Y., Mauvernay, Y., Schally, A. V., Reizenstein, P., Gastiaburu, J., Comaru-Schally, A. M., Cupissol, D., Jasmin, C., Missot, J. L., Wingen, F., Schmähl, D., Pauwels-Vergely, C., Poupon, M. -F., Gasic, T. B., Ewaskiewicz, J. I., Gasic, G. J., Pápay, J., Mauvernay, R., Schally, A., Keiling, R., Hagipantelli, R., Busuttil, M., VoVan, M. L., Misset, J. L., Lévi, F., Musset, M., Ribaud, P., Hilgard, P., Reissmann, T., Stekar, J., Voegeli, R., Den Otter, W., Maas, H. A., Dullens, H. F. J., Merriman, R. L., Tanzer, L. R., Shackelford, K. A., Bemis, K. G., Campbell, J. B., and Matsumoto, K.

Published
1988
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40. Targeting of T or NK lymphocytes against tumor cells by bispecific monoclonal antibodies: role of different triggering molecules

Author

Silvano Ferrini, Cambiaggi, A., Cantoni, C., Canevari, S., Mezzanzanica, D., Colnaghi, M. I., and Moretta, L.

Subjects
Cytotoxicity, Immunologic, Killer Cells, Natural, Lymphokines, CD3 Complex, Antigens, CD, Neoplasms, T-Lymphocytes, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, Humans
Abstract

MAbs directed against triggering surface molecules expressed by T lymphocytes (CD3, TCR, CD2, CD28) or by NK cells (CD2, CD16) are able to induce the functional program of these cells. These MAbs represent suitable reagents to construct biMAbs directed against TAA, in order to specifically target effector lymphocytes against tumor cells. Anti-CD3/anti-EGF-R biMAbs were constructed to specifically direct T lymphocytes against EGF-R+ tumor cells. Such biMAb are able to induce cytolysis of EGF-R+ tumor cell lines (A431, IGROV, KATO-III and U-87) by cytolytic CD3+ effector lymphocytes while tumor cells having low or absent expression of EGF-R were not lysed. In addition, both cytolytic T (CD8+) cells and non-cytolytic (CD4+) IL-2-expanded lymphocytes were able to secrete lymphokines upon contact with EGF-R+ tumor cells. To target NK cells against NK resistant ovarian carcinomas, we used an anti-CD16 Mab (IgG1) together with an anti-ovarian carcinoma MAb (IgG2a), to construct biMAbs using the hybrid hybridoma technique. The hybrid IgG1/IgG2a biMAb triggered the specific lysis of relevant target cells by resting NK cells and by a subset of NK clones. In addition, some TCR gamma/delta+ clones but not TCR alpha/beta+ clones could be targeted by the biMAb.

Published
1992

44. Antibody transport and internalization into tumours

Author

Matzku, S., Moldenhauer, G., Kalthoff, H., Canevari, S., Colnaghi, M., Schuhmacher, J., and Bihl, H.

Subjects
Iodine Radioisotopes, Mice, Liver, Lymphoma, health care facilities, manpower, and services, education, Indium Radioisotopes, Animals, Antibodies, Monoclonal, Neoplasms, Experimental, health care economics and organizations, Research Article
Abstract

Internalization of monoclonal antibody (MAb) conjugates is an important feature of tumour targeting, both with respect to the therapeutic action of substances coupled to the antibody and to retention of radionuclides. Problems of analysing internalization in vitro and in vivo, of manipulating internalization, and of evaluating the involvement of normal tissues are illustrated by recent experimental data and are discussed in the light of published evidence.

Published
1990

46. Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody.

Author

Canevari S, Stoter G, Arienti F, Bolis G, Colnaghi MI, Di Re EM, Eggermont AM, Goey SH, Gratama JW, Lamers CH, Canevari, S, Stoter, G, Arienti, F, Bolis, G, Colnaghi, M I, Di Re, E M, Eggermont, A M, Goey, S H, Gratama, J W, and Lamers, C H

Abstract

Background: The high frequency of relapse after induction chemotherapy of advanced ovarian carcinoma calls for new therapeutic approaches. Lysis of ovarian carcinoma cells can be achieved by retargeting of T lymphocytes using F(ab')2 fragments of the bispecific monoclonal antibody (MAb) OC/TR, which is directed to the CD3 molecule on T lymphocytes and to the folate receptor on ovarian carcinoma cells.Purpose: Our purpose was to assess in ovarian carcinoma patients the antitumor activity of in vitro-activated autologous peripheral blood T lymphocytes retargeted with OC/TR.Methods: Patients with epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages III and IV) meeting specific criteria were eligible to enter a phase II immunotherapy trial. Before immunotherapy, the 28 patients who entered the trial underwent laparotomy to reduce their tumor load and to allow measurement of all indicator lesions. They then received two cycles of five daily intraperitoneal infusions of autologous in vitro activated peripheral blood T lymphocytes retargeted with OC/TR plus recombinant interleukin 2 (IL-2) with (n = 11) or without (n = 17) a second daily infusion of OC/TR F(ab')2 and IL-2. Response to treatment could be assessed in 26 patients following explorative laparotomy; time to progression could be assessed in 27 patients.Results: Seven patients had clinical evidence of progressive disease after treatment and therefore did not undergo laparotomy. Of the 19 patients evaluated by surgery and histology, three showed complete response, one showed complete intraperitoneal response with progressive disease in retroperitoneal lymph nodes, three showed partial response, seven had stable disease, and five had progressive disease. The overall intraperitoneal response rate was 27% (95% confidence interval [CI] = 10%-44%). The complete responses seen in three patients lasted 26 months in one patient, 23 months in the second, and 18 months in the third. Two patients were not assessable for response. One of these patients had bowel perforation during catheter removal, which precluded further evaluation. The second patient was positive only by cytologic examination before immunotherapy, was tumor free at laparotomy after immunotherapy, and remained so for the entire 21 months of follow-up, as determined by cytologic examination of random biopsy specimens. The median time to disease progression in the 15 assessable patients plus those who had stable disease was 11 months (95% CI = 6-18 months). Immunotherapy-related toxic effects included mild to moderate fever, nausea, emesis, and fatigue. Anti-mouse antibodies were detectable by the end of the treatment in 21 of 25 patients tested.Conclusions: Locoregional immunotherapy of ovarian cancer with bispecific MAb-retargeted T lymphocytes can result in tumor regression. Toxicity was mild to moderate and only transient.Implications: Improvement in systemic antitumor responses is needed before this approach can prove useful as adjunctive treatment following induction chemotherapy in patients with minimal residual disease. [ABSTRACT FROM AUTHOR]

Published
1995
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47. Monitoring response to cytostatic cisplatin in a HER2(+) ovary cancer model by MRI and in vitro and in vivo MR spectroscopy.

Author

Pisanu, M E, Ricci, A, Paris, L, Surrentino, E, Liliac, L, Bagnoli, M, Canevari, S, Mezzanzanica, D, Podo, F, Iorio, E, and Canese, R

Subjects
OVARIAN cancer treatment, ANTINEOPLASTIC agents, CISPLATIN, HER2 gene, MAGNETIC resonance imaging of cancer, NUCLEAR magnetic resonance spectroscopy
Abstract

Background:Limited knowledge is available on alterations induced by cytostatic drugs on magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters of human cancers, in absence of apoptosis or cytotoxicity. We here investigated the effects of a cytostatic cisplatin (CDDP) treatment on 1H MRS and MRI of HER2-overexpressing epithelial ovarian cancer (EOC) cells and in vivo xenografts.Methods:High-resolution MRS analyses were performed on in vivo passaged SKOV3.ip cells and cell/tissue extracts (16.4 or 9.4 T). In vivo MRI/MRS quantitative analyses (4.7 T) were conducted on xenografts obtained by subcutaneous implantation of SKOV3.ip cells in SCID mice. The apparent diffusion coefficient (ADC) and metabolite levels were measured.Results:CDDP-induced cytostatic effects were associated with a metabolic shift of cancer cells towards accumulation of MRS-detected neutral lipids, whereas the total choline profile failed to be perturbed in both cultured cells and xenografts. In vivo MRI examinations showed delayed tumour growth in the CDDP-treated group, associated with early reduction of the ADC mean value.Conclusion:This study provides an integrated set of information on cancer metabolism and physiology for monitoring the response of an EOC model to a cytostatic chemotherapy, as a basis for improving the interpretation of non-invasive MR examinations of EOC patients. [ABSTRACT FROM AUTHOR]

Published
2014
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48. Choline kinase-alpha by regulating cell aggressiveness and drug sensitivity is a potential druggable target for ovarian cancer.

Author

Granata, A, Nicoletti, R, Tinaglia, V, De Cecco, L, Pisanu, M E, Ricci, A, Podo, F, Canevari, S, Iorio, E, Bagnoli, M, and Mezzanzanica, D

Abstract

Background: Aberrant choline metabolism has been proposed as a novel cancer hallmark. We recently showed that epithelial ovarian cancer (EOC) possesses an altered MRS-choline profile, characterised by increased phosphocholine (PCho) content to which mainly contribute over-expression and activation of choline kinase-alpha (ChoK-alpha).Methods: To assess its biological relevance, ChoK-alpha expression was downmodulated by transient RNA interference in EOC in vitro models. Gene expression profiling by microarray analysis and functional analysis was performed to identify the pathway/functions perturbed in ChoK-alpha-silenced cells, then validated by in vitro experiments.Results: In silenced cells, compared with control, we observed: (I) a significant reduction of both CHKA transcript and ChoK-alpha protein expression; (II) a dramatic, proportional drop in PCho content ranging from 60 to 71%, as revealed by (1)H-magnetic spectroscopy analysis; (III) a 35-36% of cell growth inhibition, with no evidences of apoptosis or modification of the main cellular survival signalling pathways; (IV) 476 differentially expressed genes, including genes related to lipid metabolism. Ingenuity pathway analysis identified cellular functions related to cell death and cellular proliferation and movement as the most perturbed. Accordingly, CHKA-silenced cells displayed a significant delay in wound repair, a reduced migration and invasion capability were also observed. Furthermore, although CHKA silencing did not directly induce cell death, a significant increase of sensitivity to platinum, paclitaxel and doxorubicin was observed even in a drug-resistant context.Conclusion: We showed for the first time in EOC that CHKA downregulation significantly decreased the aggressive EOC cell behaviour also affecting cells' sensitivity to drug treatment. These observations open the way to further analysis for ChoK-alpha validation as a new EOC therapeutic target to be used alone or in combination with conventional drugs. [ABSTRACT FROM AUTHOR]

Published
2014
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