Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer.

Abstract

PURPOSE:

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: Hernan Carol, Ingrid Boehm, C Patrick Reynolds, Min H Kang, John M Maris, Christopher L Morton, Richard Gorlick, E Anders Kolb, Stephen T Keir, Jianrong Wu, Amy E Wozniak, Yu Yang, Mark Manfredi, Jeffrey Ecsedy, Jianmin Wang, Geoffrey Neale, Peter J Houghton, Malcolm A Smith, Richard B Lock
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 5 Pg. 1291-304 (Nov 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 21448591 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Animals
• Aurora Kinase A
• Aurora Kinases
• Azepines (pharmacokinetics, pharmacology, therapeutic use)
• Cell Line, Tumor
• Child
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Female
• Gene Dosage
• Humans
• Mice
• Mice, SCID
• Neoplasms (drug therapy, genetics, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacokinetics, pharmacology, therapeutic use)