Details

Autor(en) / Beteiligte

• Gorlick, Richard
• Kolb, E. Anders
• Keir, Stephen T.
• Maris, John M.
• Reynolds, C. Patrick
• Kang, Min H.
• Carol, Hernan
• Lock, Richard
• Billups, Catherine A.
• Kurmasheva, Raushan T.
• Houghton, Peter J.
• Smith, Malcolm A.

Titel

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

Ist Teil von

• Pediatric blood & cancer, 2014-01, Vol.61 (1), p.158-164

Ort / Verlag

United States: Blackwell Publishing Ltd

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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. Pediatr Blood Cancer 2014;61:158–164. © 2013 Wiley Periodicals, Inc.