Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program

C. Patrick Reynolds, Min H. Kang, John M. Maris, E. Anders Kolb, Richard Gorlick, Jianrong Wu, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug-resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. Procedures: Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5mg/kg on an every 4 days × 3 I.V. schedule. Results: In vitro, both cabazitaxel and docetaxel had similar potency (median rIC<inf>50</inf> 0.47nM and 0.88nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. Conclusions: Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting.

Original languageEnglish (US)
Pages (from-to)1897-1905
Number of pages9
JournalPediatric Blood and Cancer
Volume62
Issue number11
DOIs
StatePublished - Nov 1 2015

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docetaxel
Microtubules
Pediatrics
Neoplasms
Heterografts
Taxoids
Ewing's Sarcoma
cabazitaxel
Vincristine

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • Taxane derivatives

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Reynolds, C. P., Kang, M. H., Maris, J. M., Kolb, E. A., Gorlick, R., Wu, J., ... Smith, M. A. (2015). Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program. Pediatric Blood and Cancer, 62(11), 1897-1905. https://doi.org/10.1002/pbc.25611

Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program. / Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Kolb, E. Anders; Gorlick, Richard; Wu, Jianrong; Kurmasheva, Raushan T.; Houghton, Peter J.; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 62, No. 11, 01.11.2015, p. 1897-1905.

Research output: Contribution to journalArticle

Reynolds, CP, Kang, MH, Maris, JM, Kolb, EA, Gorlick, R, Wu, J, Kurmasheva, RT, Houghton, PJ & Smith, MA 2015, 'Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 62, no. 11, pp. 1897-1905. https://doi.org/10.1002/pbc.25611
Reynolds, C. Patrick ; Kang, Min H. ; Maris, John M. ; Kolb, E. Anders ; Gorlick, Richard ; Wu, Jianrong ; Kurmasheva, Raushan T. ; Houghton, Peter J. ; Smith, Malcolm A. / Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2015 ; Vol. 62, No. 11. pp. 1897-1905.
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AU - Kang, Min H.

AU - Maris, John M.

AU - Kolb, E. Anders

AU - Gorlick, Richard

AU - Wu, Jianrong

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J.

AU - Smith, Malcolm A.

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N2 - Background: Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug-resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. Procedures: Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5mg/kg on an every 4 days × 3 I.V. schedule. Results: In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47nM and 0.88nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. Conclusions: Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting.

AB - Background: Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug-resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. Procedures: Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5mg/kg on an every 4 days × 3 I.V. schedule. Results: In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47nM and 0.88nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. Conclusions: Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting.

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