title: The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia.
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.
authors.affiliation: Oncology, Nerviano Medical Sciences, Nerviano, Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Casolaro
authors.forename: Josee
authors.initials: J
authors.lastname: Golay
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Roberta
authors.initials: R
authors.lastname: Ceruti
authors.forename: Veronica
authors.initials: V
authors.lastname: Patton
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cribioli
authors.forename: Alice
authors.initials: A
authors.lastname: Pezzoni
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Gemma
authors.initials: G
authors.lastname: Texido
authors.forename: Ursula
authors.initials: U
authors.lastname: Giussani
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchesi
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Silvia
authors.initials: S
authors.lastname: Bungaro
authors.forename: Gianni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.forename: Martino
authors.initials: M
authors.lastname: Introna
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
mesh_terms: D000328:Adult; D000818:Animals; D019002:CD56 Antigen; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D019002:CD56 Antigen; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011799:Quinazolines; D000097869:Polo-Like Kinase 1; C522918:NCAM1 protein, human; C560415:NMS P937