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.
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.
Authors: Harvey Wong; Edna F Choo; Bruno Alicke; Xiao Ding; Hank La; Erin McNamara; Frank-Peter Theil; Jay Tibbitts; Lori S Friedman; Cornelis E C A Hop; Stephen E Gould Journal: Clin Cancer Res Date: 2012-05-30 Impact factor: 12.531
Authors: Peter J Houghton; Christopher L Morton; Chandra Tucker; Debbie Payne; Edward Favours; Claire Cole; Richard Gorlick; E Anders Kolb; Wendong Zhang; Richard Lock; Hernan Carol; Mimi Tajbakhsh; C Patrick Reynolds; John M Maris; Joshua Courtright; Stephen T Keir; Henry S Friedman; Charles Stopford; Joseph Zeidner; Jianrong Wu; Tiebin Liu; Catherine A Billups; Javed Khan; Sherry Ansher; Jian Zhang; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2007-12 Impact factor: 3.167
Authors: Dorothea Rudolph; Martin Steegmaier; Matthias Hoffmann; Matthias Grauert; Anke Baum; Jens Quant; Christian Haslinger; Pilar Garin-Chesa; Günther R Adolf Journal: Clin Cancer Res Date: 2009-04-21 Impact factor: 12.531
Authors: Annelies G Renner; Cédric Dos Santos; Christian Recher; Christian Bailly; Laurent Créancier; Anna Kruczynski; Bernard Payrastre; Stéphane Manenti Journal: Blood Date: 2009-05-20 Impact factor: 22.113
Authors: Natalia L M Liem; Rachael A Papa; Christopher G Milross; Michael A Schmid; Mayamin Tajbakhsh; Seoyeon Choi; Carole D Ramirez; Alison M Rice; Michelle Haber; Murray D Norris; Karen L MacKenzie; Richard B Lock Journal: Blood Date: 2004-02-05 Impact factor: 22.113