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Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models

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Abstract

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

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Acknowledgements

This work was supported by a research grant from Worldwide Cancer Research. We thank Cassandra Cheng for her excellent secretarial assistance. ERN was supported by a Connaught Scholarship and a GSEF Scholarship from the University of Toronto, Canada.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, ON, M5S 2J7, Canada

    Elaine Reguera-Nuñez & Robert S. Kerbel

  2. Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, M4N 3M5, Canada

    Elaine Reguera-Nuñez, Shan Man, Ping Xu & Robert S. Kerbel

  3. Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, Room S-217, Toronto, ON, M4N 3M5, Canada

    Robert S. Kerbel

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  1. Elaine Reguera-Nuñez
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Correspondence to Robert S. Kerbel.

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Reguera-Nuñez, E., Man, S., Xu, P. et al. Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models. Angiogenesis 21, 793–804 (2018). https://doi.org/10.1007/s10456-018-9623-8

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  • DOI: https://doi.org/10.1007/s10456-018-9623-8

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