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Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel

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Abstract

Purpose

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood–brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.

Methods

Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing’s sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing’s sarcoma DM101) xenografts. The activity of cabazitaxel–cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.

Results

Cabazitaxel penetrated rapidly in the brain, with a similar brain–blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.

Conclusions

These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

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Acknowledgments

The studies were sponsored by Sanofi. The authors gratefully acknowledge D. J. Dykes from SRI and Dr J. P. Sarsat for their contribution to the glioblastomas studies; M. Malfilatre, C. Janvier, E. Boulcourt-Sambou, Dr L. Vincent and Dr L. Calvet for their contribution to the pediatric tumor cell-based xenograft studies; Dr E. Bruckheimer from Champions Oncology, F. Windenberger and O. Couder for their contribution to the pediatric PDX studies; Drs G. Sanderink, Y. Archimbaud, P. Gires, R. Pellerin, L. Ridoux, O. Pasquier, M. Marietta and M. H. Pascual for their contribution to the PK studies of cabazitaxel; Drs V. Benning and E. Beys for their contribution to the preclinical development of cabazitaxel; and Dr M. Nunes for his contribution to the combination study. The authors received support in the form of medical writing services from Ben Caldwell of MediTech Media, funded by Sanofi.

Conflict of interest

DS, SS, MCB and PV have a remunerated employment position with Sanofi to disclose; DS has stock ownership in Sanofi.

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  1. M.-C. Bissery

    Present address: Genticel, 112–114 Rue de la Boetie, 75008, Paris, France

Authors and Affiliations

  1. Sanofi DSAR, 3, digue d’Alfortville, 94140, Alfortville, France

    D. Sémiond

  2. Sanofi Oncology, 13 quai Jules Guesde, BP 14, 94403, Vitry-sur-Seine Cedex, France

    S. S. Sidhu, M.-C. Bissery & P. Vrignaud

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  1. D. Sémiond
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Correspondence to P. Vrignaud.

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Sémiond, D., Sidhu, S.S., Bissery, MC. et al. Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel. Cancer Chemother Pharmacol 72, 515–528 (2013). https://doi.org/10.1007/s00280-013-2214-x

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