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

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 I.V 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 nM to 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 (2 neuroblastoma, 1 glioblastoma, and 1 rhabdomyosarcoma) and 1 of 4 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.

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments

“…Although it was not a clinical study per se, the drug was tested against a panel of xenographic tumors derived from 24 different pediatric cell lines (including six OS). BI 6727 induced regressions in a minority of tumors, with objective responses observed only for neuroblastoma [3], which led the authors to point to the possibility that the antitumor activity of BI 6727 against childhood cancers may be overrated because mice tolerate higher systemic exposure to BI 6727 compared with humans. Interestingly, in the near future, a trial will be conducted to collect data on the safety, tolerability, toxicity, efficacy, pharmacokinetics, and pharmacodynamics of BI 6727 in pediatric solid tumors and leukemia, particularly for patients with advanced cancers for whom no therapy is known (http:// clinicaltrials.gov/ct2/show/NCT01971476?term = volasertib + children&rank = 2).…”

“…Elevated levels of PLK1 have been described in a variety of pediatric malignancies, including OS cell lines and resected tumor samples [2,3]. This kinase plays an essential role during cell division [4], and its interference by shRNA [2,5] or the small ATP-competitive inhibitor BI 2536 [6,7] has been shown to promote mitotic arrest and cell death in OS cells, pointing to PLK1 as a pertinent therapeutic target.…”

Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

“…The significance of developing PLK1 inhibitor-based combinations is underlined by a recent study of the Pediatric Preclinical Testing Program showing only modest single-agent antitumor activity of BI 6727 against the pediatric solid tumor xenograft panel. 27 This underscores the need for rational drug combinations, for example, together with microtubule-interfering drugs as demonstrated in this study. Synthetic lethal drug combinations are particularly interesting in the current era of molecular targeted therapies, as they offer the advantage of yielding synergistic antitumor activity at relatively low concentrations of each drug without causing additive toxicity.…”

PLK1, A Potential Target for Cancer Therapy

“…Volasertib (BI6727) is another promising PLK1 inhibitor. Several preclinical experiments have demonstrated that BI6727 is highly efficacious in inducing tumor regression [116], [132], [133], [134]. As a result, this agent has recently been awarded the “Breakthrough Therapy Status” by the Food and Drug Administration for its significant benefit in treating acute myeloid leukemia patients [135].…”