Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program

Pediatr Blood Cancer. 2014 Jan;61(1):158-64. doi: 10.1002/pbc.24616. Epub 2013 Aug 19.

Abstract

Background: Volasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP.

Procedures: Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels administered IV at a dose of 30 mg/kg (solid tumors) or 15 mg/kg (ALL models) using a q7dx3 schedule.

Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1 nM, (range 6.0-135 nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts.

Conclusions: Volasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied.

Keywords: Plk inhibitor; developmental therapeutics; preclinical testing.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, SCID
  • Neoplasms, Experimental / drug therapy*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Pteridines / pharmacokinetics
  • Pteridines / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BI 6727
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pteridines
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1