Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)

Pediatr Blood Cancer. 2010 Jul 15;55(1):26-34. doi: 10.1002/pbc.22430.

Abstract

Background: MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis.

Procedures: MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 microM and was tested against the PPTP in vivo panels at a dose of 20 mg/kg administered orally twice daily x 5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts.

Results: MLN8237 had a median IC(50) of 61 nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n = 4) or maintained CR (n = 2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma.

Conclusions: The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase A
  • Aurora Kinases
  • Azepines / administration & dosage
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / enzymology
  • Neoplasms, Experimental / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Azepines
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • AURKA protein, human
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases