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Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model

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Abstract

Purpose

Everolimus (RAD001, Afinitor) is an mTORC1 pathway inhibitor, and vatalanib (PTK/ZK) is a pan VEGF-R tyrosine kinase inhibitor (TKI). These two drugs have been shown to have overlapping but also distinct anti-angiogenic effects. Consequently, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of their combination in vivo.

Methods

Murine melanoma B16/BL6 cells were grown orthotopically in BL6/C57 mice by injection into the derma of both ears to create a primary tumour which metastasized rapidly to the cervical lymph nodes. Mice were treated daily p.o. with PTK/ZK (100 mg/kg) or everolimus (1 mg/kg) or their combination, and anti-tumour efficacy (PD) assessed. In the same model, plasma PK of everolimus was measured following single doses of the monotherapy or combination schedules.

Results

Two independent experiments showed that combination of everolimus and PTK/ZK caused at least additive increases in anti-tumour activity compared to either monotherapy, without increases in toxicity. Pooling the data to improve the statistical power demonstrated the interactions to be synergistic. PK modelling showed that although PTK/ZK increased everolimus plasma concentrations by about twofold, this PK drug–drug interaction could not account for the increased anti-tumour effect of the combination. Modelling of the PTK/ZK dose–response curve in this model suggested that any effect of everolimus on the PK of PTK/ZK was unlikely to affect efficacy. Measurement of changes in tumour and plasma VEGF levels at the endpoint of therapy confirmed earlier observations of differential effects of these two agents.

Conclusions

The combination of everolimus and PTK/ZK hold promise for the treatment of human cancers.

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Abbreviations

bFGF:

Basic fibroblast growth factor

LN:

Lymph node

VEGF:

Vascular endothelial growth factor

VEGF-R:

Vascular endothelial growth factor receptor

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Acknowledgments

We thank Marc Hattenberger, Melanie Muller, Hans-Peter Mueller, Andreas Theuer, Beatrice Probst, Marina Maurer, and Julianne Vaxelaire for technical assistance.

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Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Oncology Research, 4002, Basel, Switzerland

    Terence O’Reilly, Heidi A. Lane, Jeanette M. Wood, Christian Schnell, Amanda Littlewood-Evans, Josef Brueggen & Paul M. J. McSheehy

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  1. Terence O’Reilly
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  2. Heidi A. Lane
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  3. Jeanette M. Wood
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  4. Christian Schnell
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  7. Paul M. J. McSheehy
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Correspondence to Paul M. J. McSheehy.

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O’Reilly, T., Lane, H.A., Wood, J.M. et al. Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. Cancer Chemother Pharmacol 67, 193–200 (2011). https://doi.org/10.1007/s00280-010-1307-z

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  • DOI: https://doi.org/10.1007/s00280-010-1307-z

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