The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia
CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic bla...
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| Veröffentlicht in: | PloS one 2013-03, Vol.8 (3), p.e58424-e58424 |
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| creator | Casolaro, Alessia Golay, Josee Albanese, Clara Ceruti, Roberta Patton, Veronica Cribioli, Sabrina Pezzoni, Alice Losa, Marco Texido, Gemma Giussani, Ursula Marchesi, Francesco Amboldi, Nadia Valsasina, Barbara Bungaro, Silvia Cazzaniga, Gianni Rambaldi, Alessandro Introna, Martino Pesenti, Enrico Alzani, Rachele |
| description | CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML. |
| doi_str_mv | 10.1371/journal.pone.0058424 |
| format | Article |
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We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0058424</identifier><identifier>PMID: 23520509</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute myeloid leukemia ; Adult ; Animal tissues ; Animals ; Biology ; Biomarkers ; Cancer therapies ; CD56 Antigen ; Cell cycle ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - metabolism ; Central nervous system ; Cytarabine ; Enzyme inhibitors ; Hematology ; Humans ; Inhibitors ; Karyotypes ; Kinases ; Laboratory animals ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - enzymology ; Leukemia, Myeloid, Acute - pathology ; Medicine ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Multidrug resistance ; Mutation ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - enzymology ; Neoplasms, Experimental - pathology ; Oncology ; Pathology ; Patients ; Pediatrics ; Polo-like kinase ; Polo-Like Kinase 1 ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - metabolism ; Pyrazoles - pharmacology ; Quinazolines - pharmacology ; Schedules ; Tumor Cells, Cultured ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e58424-e58424</ispartof><rights>2013 Casolaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Casolaro et al 2013 Casolaro et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a0335a724d6ed46bbf1588ebbf8e62908ca8dbd2879e2b3ba546aa7a0f13af213</citedby><cites>FETCH-LOGICAL-c526t-a0335a724d6ed46bbf1588ebbf8e62908ca8dbd2879e2b3ba546aa7a0f13af213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592825/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592825/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23520509$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Casolaro, Alessia</creatorcontrib><creatorcontrib>Golay, Josee</creatorcontrib><creatorcontrib>Albanese, Clara</creatorcontrib><creatorcontrib>Ceruti, Roberta</creatorcontrib><creatorcontrib>Patton, Veronica</creatorcontrib><creatorcontrib>Cribioli, Sabrina</creatorcontrib><creatorcontrib>Pezzoni, Alice</creatorcontrib><creatorcontrib>Losa, Marco</creatorcontrib><creatorcontrib>Texido, Gemma</creatorcontrib><creatorcontrib>Giussani, Ursula</creatorcontrib><creatorcontrib>Marchesi, Francesco</creatorcontrib><creatorcontrib>Amboldi, Nadia</creatorcontrib><creatorcontrib>Valsasina, Barbara</creatorcontrib><creatorcontrib>Bungaro, Silvia</creatorcontrib><creatorcontrib>Cazzaniga, Gianni</creatorcontrib><creatorcontrib>Rambaldi, Alessandro</creatorcontrib><creatorcontrib>Introna, Martino</creatorcontrib><creatorcontrib>Pesenti, Enrico</creatorcontrib><creatorcontrib>Alzani, Rachele</creatorcontrib><title>The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML.</description><subject>Acute myeloid leukemia</subject><subject>Adult</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Cancer therapies</subject><subject>CD56 Antigen</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - antagonists & inhibitors</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Central nervous system</subject><subject>Cytarabine</subject><subject>Enzyme inhibitors</subject><subject>Hematology</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Karyotypes</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Multidrug resistance</subject><subject>Mutation</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - enzymology</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Oncology</subject><subject>Pathology</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Polo-like kinase</subject><subject>Polo-Like Kinase 1</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Pyrazoles - pharmacology</subject><subject>Quinazolines - pharmacology</subject><subject>Schedules</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor 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Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Casolaro, Alessia</au><au>Golay, Josee</au><au>Albanese, Clara</au><au>Ceruti, Roberta</au><au>Patton, Veronica</au><au>Cribioli, Sabrina</au><au>Pezzoni, Alice</au><au>Losa, Marco</au><au>Texido, Gemma</au><au>Giussani, Ursula</au><au>Marchesi, Francesco</au><au>Amboldi, Nadia</au><au>Valsasina, Barbara</au><au>Bungaro, Silvia</au><au>Cazzaniga, Gianni</au><au>Rambaldi, Alessandro</au><au>Introna, Martino</au><au>Pesenti, Enrico</au><au>Alzani, Rachele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-03-08</date><risdate>2013</risdate><volume>8</volume><issue>3</issue><spage>e58424</spage><epage>e58424</epage><pages>e58424-e58424</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23520509</pmid><doi>10.1371/journal.pone.0058424</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-03, Vol.8 (3), p.e58424-e58424 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1330882403 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acute myeloid leukemia Adult Animal tissues Animals Biology Biomarkers Cancer therapies CD56 Antigen Cell cycle Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - metabolism Central nervous system Cytarabine Enzyme inhibitors Hematology Humans Inhibitors Karyotypes Kinases Laboratory animals Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - enzymology Leukemia, Myeloid, Acute - pathology Medicine Mice Mice, Inbred NOD Mice, SCID Multidrug resistance Mutation Neoplasms, Experimental - drug therapy Neoplasms, Experimental - enzymology Neoplasms, Experimental - pathology Oncology Pathology Patients Pediatrics Polo-like kinase Polo-Like Kinase 1 Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - metabolism Pyrazoles - pharmacology Quinazolines - pharmacology Schedules Tumor Cells, Cultured Tumors Xenograft Model Antitumor Assays |
| title | The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia |
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