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Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.
Andersson, E I; Pützer, S; Yadav, B; Dufva, O; Khan, S; He, L; Sellner, L; Schrader, A; Crispatzu, G; Oles, M; Zhang, H; Adnan-Awad, S; Lagström, S; Bellanger, D; Mpindi, J P; Eldfors, S; Pemovska, T; Pietarinen, P; Lauhio, A; Tomska, K; Cuesta-Mateos, C; Faber, E; Koschmieder, S; Brümmendorf, T H; Kytölä, S; Savolainen, E-R; Siitonen, T; Ellonen, P; Kallioniemi, O; Wennerberg, K; Ding, W; Stern, M-H; Huber, W; Anders, S; Tang, J; Aittokallio, T; Zenz, T; Herling, M; Mustjoki, S.
Afiliación
  • Andersson EI; Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • Pützer S; Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), CMMC, Center for Molecular Medicine, University of Cologne, Germany.
  • Yadav B; Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • Dufva O; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Khan S; Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • He L; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Sellner L; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Schrader A; Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
  • Crispatzu G; Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
  • Oles M; Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), CMMC, Center for Molecular Medicine, University of Cologne, Germany.
  • Zhang H; Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), CMMC, Center for Molecular Medicine, University of Cologne, Germany.
  • Adnan-Awad S; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Lagström S; Division of Hematology, Mayo Clinic, Rochester, MN, USA.
  • Bellanger D; Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • Mpindi JP; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Eldfors S; Institut Curie, INSERM U830, PSL Research University, Paris, France.
  • Pemovska T; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Pietarinen P; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Lauhio A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Tomska K; Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • Cuesta-Mateos C; Department of Medicine, Division of Infectious Disease, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
  • Faber E; Department of Translational Oncology and Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
  • Koschmieder S; Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
  • Brümmendorf TH; Departamento de Immunología, Hospital Universitario de la Princesa, Madrid, Spain.
  • Kytölä S; Department of Hemato-oncology, University Hospital Olomouc, Olomouc, Czech Republic.
  • Savolainen ER; Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
  • Siitonen T; Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
  • Ellonen P; Helsinki University Central Hospital (HUCH), Laboratory of Genetics, HUSLAB, Helsinki, Finland.
  • Kallioniemi O; Nordlab Oulu, Hematology Laboratory, MRC Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • Wennerberg K; Department of Hematology, Oulu University Hospital, MRC Oulu, University of Oulu, Oulu, Finland.
  • Ding W; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Stern MH; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Huber W; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Anders S; Division of Hematology, Mayo Clinic, Rochester, MN, USA.
  • Tang J; Institut Curie, INSERM U830, PSL Research University, Paris, France.
  • Aittokallio T; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Zenz T; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Herling M; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Mustjoki S; Department of Mathematics and Statistics, University of Turku, Turku, Finland.
Leukemia ; 32(3): 774-787, 2018 03.
Article en En | MEDLINE | ID: mdl-28804127
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Leucemia Prolinfocítica de Células T / Biomarcadores de Tumor / Resistencia a Antineoplásicos / Ensayos Analíticos de Alto Rendimiento / Mutación / Antineoplásicos Tipo de estudio: Diagnostic_studies Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Leucemia Prolinfocítica de Células T / Biomarcadores de Tumor / Resistencia a Antineoplásicos / Ensayos Analíticos de Alto Rendimiento / Mutación / Antineoplásicos Tipo de estudio: Diagnostic_studies Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido