Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background: Volasertib (BI 6727) is a potent inhibitor of Pololike 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 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC<inf>50</inf> value of 14.1nM, (range 6.0-135nM). 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.

Original languageEnglish (US)
Pages (from-to)158-164
Number of pages7
JournalPediatric Blood and Cancer
Volume61
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Pediatrics
Heterografts
Neoplasms
Glioblastoma
Neuroblastoma
Cell Line
BI 6727
polo-like kinase 1
Rhabdomyosarcoma
Inhibitory Concentration 50
Appointments and Schedules
Phosphotransferases
Pharmacokinetics
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
Growth
In Vitro Techniques

Keywords

  • Developmental therapeutics
  • Plk inhibitor
  • Preclinical testing

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Gorlick, R., Kolb, E. A., Keir, S. T., Maris, J. M., Reynolds, C. P., Kang, M. H., ... Smith, M. A. (2014). Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program. Pediatric Blood and Cancer, 61(1), 158-164. https://doi.org/10.1002/pbc.24616

Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program. / 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.

In: Pediatric Blood and Cancer, Vol. 61, No. 1, 2014, p. 158-164.

Research output: Contribution to journalArticle

Gorlick, R, Kolb, EA, Keir, ST, Maris, JM, Reynolds, CP, Kang, MH, Carol, H, Lock, R, Billups, CA, Kurmasheva, RT, Houghton, PJ & Smith, MA 2014, 'Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 61, no. 1, pp. 158-164. https://doi.org/10.1002/pbc.24616
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. / Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2014 ; Vol. 61, No. 1. pp. 158-164.
@article{7c7b74debcac4c63b2cbe8ab91b44475,
title = "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 Pololike 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 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). 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 = "Developmental therapeutics, Plk inhibitor, Preclinical testing",
author = "Richard Gorlick and Kolb, {E. Anders} and Keir, {Stephen T.} and Maris, {John M.} and Reynolds, {C. Patrick} and Kang, {Min H.} and Hernan Carol and Richard Lock and Billups, {Catherine A.} and Kurmasheva, {Raushan T.} and Houghton, {Peter J.} and Smith, {Malcolm A.}",
year = "2014",
doi = "10.1002/pbc.24616",
language = "English (US)",
volume = "61",
pages = "158--164",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the pediatric preclinical testing program

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Keir, Stephen T.

AU - Maris, John M.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Carol, Hernan

AU - Lock, Richard

AU - Billups, Catherine A.

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

PY - 2014

Y1 - 2014

N2 - Background: Volasertib (BI 6727) is a potent inhibitor of Pololike 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 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). 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.

AB - Background: Volasertib (BI 6727) is a potent inhibitor of Pololike 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 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). 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.

KW - Developmental therapeutics

KW - Plk inhibitor

KW - Preclinical testing

UR - http://www.scopus.com/inward/record.url?scp=84891670915&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891670915&partnerID=8YFLogxK

U2 - 10.1002/pbc.24616

DO - 10.1002/pbc.24616

M3 - Article

C2 - 23956067

AN - SCOPUS:84891670915

VL - 61

SP - 158

EP - 164

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 1

ER -