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1. A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

Author

Abate, F, Todaro, M, van der Krogt, J-A, Boi, M, Landra, I, Machiorlatti, R, Tabbò, F, Messana, K, Abele, C, Barreca, A, Novero, D, Gaudiano, M, Aliberti, S, Di Giacomo, F, Tousseyn, T, Lasorsa, E, Crescenzo, R, Bessone, L, Ficarra, E, Acquaviva, A, Rinaldi, A, Ponzoni, M, Longo, D L, Aime, S, Cheng, M, Ruggeri, B, Piccaluga, P P, Pileri, S, Tiacci, E, Falini, B, Pera-Gresely, B, Cerchietti, L, Iqbal, J, Chan, W C, Shultz, L D, Kwee, I, Piva, R, Wlodarska, I, Rabadan, R, Bertoni, F, and Inghirami, G

Published
2015
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2. Anaplastic lymphoma kinase in human cancer

Author

Barreca, A., Lasorsa, E., Riera, L., Machiorlatti, R., Piva, R., Ponzoni, M., Kwee, I., Bertoni, F., Piccaluga, P.P., Pileri, S.A., Inghirami, G.C.B.A., Chiarle, R., Cuccuru, G., Inghirami, G., Martinoglio, B., Medico, E., Pellegrino, E., Ruberto, M.L., Voena, C., Fornari, A., Novero, D., Chilosi, M., Zamó, A., Facchetti, F., Lonardi, S., De Chiara, A., Fulciniti, F., Doglioni, C., Agnelli, L., Neri, A., Todoerti, K., Pileri, S., Falini, B., Tiacci, E., Van Loo, P., Tousseyn, T., De Wolf-Peeters, C., Geissinger, E., Muller-Hermelink, H.K., Rosenwald, A., Piris, M.A., Maria, E.R., Barreca A, Lasorsa E, Riera L, Machiorlatti R, Piva R, Ponzoni M, Kwee I, Bertoni F, Piccaluga PP, Pileri SA, Inghirami G, and the European T-Cell Lymphoma Study Group, Barreca, A, Lasorsa, E, Riera, L, Machiorlatti, R, Piva, R, Ponzoni, Maurilio, Kwee, I, Bertoni, F, Piccaluga, Pp, Pileri, Sa, and Inghirami, G.

Subjects
Transcriptional Activation, Lymphoma, kinase, Settore MED/06 - Oncologia Medica, Pyridines, Receptor Protein-Tyrosine Kinases, Antineoplastic Agents, Receptor tyrosine kinase, Translocation, Genetic, CSK Tyrosine-Protein Kinase, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, Endocrinology, Crizotinib, Piperidines, Neoplasms, Proto-Oncogene Proteins, hemic and lymphatic diseases, medicine, cancer, Anaplastic lymphoma kinase, Humans, Anaplastic Lymphoma Kinase, anaplastic lymphoma, Molecular Biology, Anaplastic large-cell lymphoma, Nucleophosmin, biology, Phospholipase C gamma, ALK, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, medicine.disease, BCL10, Up-Regulation, src-Family Kinases, Mutation, Cancer research, biology.protein, Pyrazoles, Signal transduction, medicine.drug, Signal Transduction
Abstract

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)–ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK–RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.

Published
2011

4. A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

Author

Thomas Tousseyn, Elena Lasorsa, M. Ponzoni, Cristina Abele, Andrea Acquaviva, S. A. Pileri, Pier Paolo Piccaluga, Domenico Novero, Maria Todaro, Antonella Barreca, Francesco Abate, Ivo Kwee, Giorgio Inghirami, F Di Giacomo, Javeed Iqbal, Indira Landra, Raul Rabadan, Silvio Aime, Wing C. Chan, Rodolfo Machiorlatti, Mangeng Cheng, Michela Boi, Enrico Tiacci, B Pera-Gresely, Francesco Bertoni, Leonard D. Shultz, J-A van der Krogt, Katia Messana, Bruce Ruggeri, Brunangelo Falini, Sabrina Aliberti, Fabrizio Tabbò, Marcello Gaudiano, Luca Bessone, Roberto Piva, R Crescenzo, Andrea Rinaldi, Iwona Wlodarska, Dario Livio Longo, Elisa Ficarra, Leandro Cerchietti, Abate, F., Todaro, M., Van Der Krogt, J.-A., Boi, M., Landra, I., Machiorlatti, R., Tabbò, F., Messana, K., Abele, C., Barreca, A., Novero, D., Gaudiano, M., Aliberti, S., Di Giacomo, F., Tousseyn, T., Lasorsa, E., Crescenzo, R., Bessone, L., Ficarra, E., Acquaviva, A., Rinaldi, A., Ponzoni, M., Longo, D.L., Aime, S., Cheng, M., Ruggeri, B., Piccaluga, P.P., Pileri, S., Tiacci, E., Falini, B., Pera-Gresely, B., Cerchietti, L., Iqbal, J., Chan, W.C., Shultz, L.D., Kwee, I., Piva, R., Wlodarska, I., Rabadan, R., Bertoni, F., Inghirami, G., The European T-cell Lymphoma Study Group [.., Agostinelli, C., ], European T-cell Lymphoma Study Group, Cavallo, F., Chiesa, N., Fienga, A., di Giacomo, F., Marchiorlatti, R., Martinoglio, B., Medico, E., Ferrero, GB., Mereu, E., Pellegrino, E., Scafò, I., Spaccarotella, E., Ubezzi, I., Urigu, S., Chiapella, A., Vitolo, U., Agnelli, L., Neri, A., Chilosi£££Anna Caliò Marco£££ AC., Zamó, A., Facchetti, F., Lonardi, S., De Chiara, A., Fulciniti, F., Ferreri, A., Piccaluga, PP., Van Loo, P., De Wolf-Peeters, C., Geissinger, E., Muller-Hermelink, HK., Rosenwald, A., Piris, MA., Rodriguez, ME., Chiattone, C., Paes, RA., Abate, F, Todaro, M, van der Krogt, Ja, Boi, M, Landra, I, Machiorlatti, R, Tabbò, F, Messana, K, Abele, C, Barreca, A, Novero, D, Gaudiano, M, Aliberti, S, Di Giacomo, F, Tousseyn, T, Lasorsa, E, Crescenzo, R, Bessone, L, Ficarra, E, Acquaviva, A, Rinaldi, A, Ponzoni, M, Longo, Dl, Aime, S, Cheng, M, Ruggeri, B, Piccaluga, Pp, Pileri, S, Tiacci, E, Falini, B, Pera-Gresely, B, Cerchietti, L, Iqbal, J, Chan, Wc, Shultz, Ld, Kwee, I, Piva, R, Wlodarska, I, Rabadan, R, Bertoni, F, Inghirami, G, and andThe European T-cell Lymphoma Study, Group

Subjects
Pathology, Cancer Research, Lymphoma, TRAF1, Messenger, Drug Resistance, Translocation, Genetic, Fusion gene, Mice, Mice, Inbred NOD, hemic and lymphatic diseases, Tumor Cells, Cultured, Anaplastic lymphoma kinase, Anaplastic, Anaplastic Lymphoma Kinase, Anaplastic large-cell lymphoma, Animals, Blotting, Western, Flow Cytometry, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Immunoprecipitation, In Situ Hybridization, Fluorescence, Lymphoma, Large-Cell, Anaplastic, NF-kappa B, Proteasome Inhibitors, Proto-Oncogene Proteins c-myc, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptor Protein-Tyrosine Kinases, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 1, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, In Situ Hybridization, Hematology, Cultured, Blotting, Medicine (all), Large-Cell, Tumor Cells, Proteasome Inhibitor, Receptor Protein-Tyrosine Kinase, Oncology, Western, Human, medicine.medical_specialty, fusion detection tool, Xenograft Model Antitumor Assay, medicine.drug_class, Translocation, Anesthesiology and Pain Medicine, Biology, anaplastic large-cell lymphomas (ALCL), RNA-Seq data, Fluorescence, Article, Genetic, Internal medicine, PRDM1, medicine, traslocation, Animal, Repressor Protein, medicine.disease, ALK inhibitor, anaplastic lymphoma kinase (ALK), Cancer research, Inbred NOD, RNA, Neoplasm, Positive Regulatory Domain I-Binding Factor 1, Lymphoma, Large-Cell, Anaplastic/drug therapy, Lymphoma, Large-Cell, Anaplastic/genetics, NF-kappa B/genetics, NF-kappa B/metabolism, Proteasome Inhibitors/pharmacology, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/metabolism, RNA, Messenger/genetics, Receptor Protein-Tyrosine Kinases/genetics, Receptor Protein-Tyrosine Kinases/metabolism, Repressor Proteins/genetics, Repressor Proteins/metabolism, TNF Receptor-Associated Factor 1/genetics, TNF Receptor-Associated Factor 1/metabolism, Translocation, Genetic/genetics, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism
Abstract

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kappa B (NF kappa B) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NF kappa B gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NF kappa B signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.

Published
2015

5. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts

Author

Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, De Wolf Peeters, Christiane, Tousseyn, Thomas, Van Loo, Peter, Geissinger, Eva, Muller Hermelink, Hans Konrad, Rosenwald, Andreas, Matolcsy, Andras, Piris, Miguel Angel, Rodriguez Pinilla, Maria E., AGOSTINELLI, CLAUDIO, PICCALUGA, PIER PAOLO, PILERI, STEFANO, Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, Agostinelli, Claudio, Piccaluga, Pier Paolo, Pileri, Stefano, De Wolf-Peeters, Christiane, Tousseyn, Thoma, Van Loo, Peter, Geissinger, Eva, Muller-Hermelink, Hans Konrad, Rosenwald, Andrea, Matolcsy, Andra, Piris, Miguel Angel, Rodriguez-Pinilla, Maria E., Scarfò, I, Pellegrino, E, Mereu, E, Kwee, I, Agnelli, L, Bergaggio, E, Garaffo, G, Vitale, N, Caputo, M, Machiorlatti, R, Circosta, P, Abate, F, Barreca, A, Novero, D, Mathew, S, Rinaldi, A, Tiacci, E, Serra, S, Deaglio, S, Neri, A, Falini, B, Rabadan, R, Bertoni, F, Inghirami, G, Piva, R, the European T-Cell Lymphoma Study, Group, Doglioni, C, and Ponzoni, M

Subjects
0301 basic medicine, Untranslated region, Receptor, ErbB-4, Messenger, Mice, SCID, Biochemistry, Mice, 0302 clinical medicine, 5' Untranslated Region, HEK293 Cell, Mutant Protein, Mice, Inbred NOD, hemic and lymphatic diseases, 5' Untranslated RegionsAnimalsCodon, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, NIH 3T3 Cell, Regulation of gene expression, TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor, Hematology, Long terminal repeat, Large-Cell, Gene Expression Regulation, Neoplastic, Receptor Protein-Tyrosine Kinase, Codon, Nonsense, 030220 oncology & carcinogenesis, Lymphoma, Large-Cell, Anaplastic, Human, Molecular Sequence Data, Immunology, ErbB-4RNA, Mice, Transgenic, Biology, 03 medical and health sciences, Complementary DNA, Animals, Humans, RNA, Messenger, Gene, NonsenseGene Expression Regulation, NeoplasticHEK293 CellsHumansLymphoma, Animal, Receptor Protein-Tyrosine Kinases, RNA, Cell Biology, Molecular biology, Gene expression profiling, HEK293 Cells, 030104 developmental biology, Inbred NODMice, NIH 3T3 Cells, Mutant Proteins, SCIDMice, AnaplasticMiceMice, 5' Untranslated Regions, 5' Untranslated RegionsAnimalsCodon, NonsenseGene Expression Regulation, NeoplasticHEK293 CellsHumansLymphoma, Large-Cell, AnaplasticMiceMice, Inbred NODMice, SCIDMice, TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor, ErbB-4RNA, Messenger
Abstract

Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions. © 2016 by The American Society of Hematology.

Published
2016

6. Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Author

Circosta P, Elia AR, Landra I, Machiorlatti R, Todaro M, Aliberti S, Brusa D, Deaglio S, Chiaretti S, Bruna R, Gottardi D, Massaia M, Giacomo FD, Guarini AR, Foà R, Kyriakides PW, Bareja R, Elemento O, Chichili GR, Monteleone E, Moore PA, Johnson S, Bonvini E, Cignetti A, and Inghirami G

Abstract

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4 + cells into cytotoxic effectors required the presence of CD8 + cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.

Published
2018
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7. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas.

Author

Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, Tabbò F, Gaudiano M, Zahreddine H, Goldstein RL, Patel J, Taldone T, Chiosis G, Ladetto M, Ghione P, Machiorlatti R, Elemento O, Inghirami G, Melnick A, Borden KL, and Cerchietti L

Subjects
Active Transport, Cell Nucleus drug effects, Cell Line, Tumor, Cell Nucleus pathology, Humans, Lymphoma, B-Cell pathology, Neoplasm Proteins metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Nucleus metabolism, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell metabolism, Neoplasm Proteins antagonists & inhibitors, RNA, Messenger metabolism, RNA, Neoplasm metabolism
Abstract

Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo., (© 2016 by The American Society of Hematology.)

Published
2016
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8. CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.

Author

Cheng M, Quail MR, Gingrich DE, Ott GR, Lu L, Wan W, Albom MS, Angeles TS, Aimone LD, Cristofani F, Machiorlatti R, Abele C, Ator MA, Dorsey BD, Inghirami G, and Ruggeri BA

Subjects
Administration, Oral, Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Benzocycloheptenes chemistry, Biological Availability, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Female, Humans, Immunoblotting, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit genetics, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse metabolism, Lymphoma, Large B-Cell, Diffuse pathology, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, Nude, Mice, SCID, Molecular Structure, Neoplasms metabolism, Neoplasms pathology, Neuroblastoma drug therapy, Neuroblastoma metabolism, Neuroblastoma pathology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines chemistry, Receptor Protein-Tyrosine Kinases metabolism, Antineoplastic Agents pharmacology, Benzocycloheptenes pharmacology, Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Xenograft Model Antitumor Assays
Abstract

Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice.

Published
2012
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9. Anaplastic lymphoma kinase in human cancer.

Author

Barreca A, Lasorsa E, Riera L, Machiorlatti R, Piva R, Ponzoni M, Kwee I, Bertoni F, Piccaluga PP, Pileri SA, and Inghirami G

Subjects
Anaplastic Lymphoma Kinase, Antineoplastic Agents pharmacology, CSK Tyrosine-Protein Kinase, Crizotinib, Humans, Intracellular Signaling Peptides and Proteins metabolism, Lymphoma genetics, Mutation, Neoplasms genetics, Neoplasms metabolism, Phosphatidylinositol 3-Kinases metabolism, Phospholipase C gamma metabolism, Piperidines pharmacology, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Pyrazoles, Pyridines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics, Signal Transduction, Transcriptional Activation, Translocation, Genetic, Up-Regulation genetics, src-Family Kinases, Lymphoma metabolism, Receptor Protein-Tyrosine Kinases metabolism
Abstract

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)-ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK-RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.

Published
2011
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