title: Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer.
abstract: OBJECTIVE
  To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies.
  
  
  METHODS
  The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies were undertaken.
  
  
  RESULTS
  In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines. MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD. In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD. Pharmacokinetic studies at 0.5MTD demonstrated a T                            (max) of 0.5 h, C                            (max) of 24.8 μM, AUC((0-24)) of 60.3 μM h, and 12 h trough level of 1.2 μM. Mitotic indices increased 6-12 h after MLN8237 administration. AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number.
  
  
  CONCLUSIONS
  Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14). This report confirms the significant activity against both solid tumor and ALL xenografts at the MTD, with a steep dose response. These data support clinical development of MLN8237 in childhood cancer. Because of the steep dose-response relationship, such studies should target achieving trough levels of 1 μM or higher for sustained periods of treatment.
authors: Leukaemia Biology Program, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Randwick, NSW 2031, Australia.
authors: Hernan
authors: H
authors: Carol
authors: Ingrid
authors: I
authors: Boehm
authors: C Patrick
authors: CP
authors: Reynolds
authors: Min H
authors: MH
authors: Kang
authors: John M
authors: JM
authors: Maris
authors: Christopher L
authors: CL
authors: Morton
authors: Richard
authors: R
authors: Gorlick
authors: E Anders
authors: EA
authors: Kolb
authors: Stephen T
authors: ST
authors: Keir
authors: Jianrong
authors: J
authors: Wu
authors: Amy E
authors: AE
authors: Wozniak
authors: Yu
authors: Y
authors: Yang
authors: Mark
authors: M
authors: Manfredi
authors: Jeffrey
authors: J
authors: Ecsedy
authors: Jianmin
authors: J
authors: Wang
authors: Geoffrey
authors: G
authors: Neale
authors: Peter J
authors: PJ
authors: Houghton
authors: Malcolm A
authors: MA
authors: Smith
authors: Richard B
authors: RB
authors: Lock
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002648:Child; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; C550258:MLN 8237; D011743:Pyrimidines; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases