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Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer

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Abstract

An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy—the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype.

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Acknowledgments

This work was supported by grants to RSK from the Canadian Institutes of Health Research (CIHR) and the National Institutes of Health (NIH), USA (CA-41233) and the Canadian Breast Cancer Foundation (CBCF). RSK is a Canada Research Chair in Tumor Biology, Angiogenesis, and Antiangiogenic Therapy. M.L. Jaramillo, C. Collins, M. Banville and M.D. O'Connor-McCourt were supported by the NRC Genome Health Initiative Cancer Program (NRC publication number NRC5322).

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Authors and Affiliations

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

    William Cruz-Muñoz, Teresa Di Desidero, Shan Man, Ping Xu, Kae Hashimoto & Robert S. Kerbel

  2. National Research Council of Canada, Human Health Therapeutics, NRCC, Montreal, QC, Canada

    Maria Luz Jaramillo, Catherine Collins, Myriam Banville & Maureen D. O’Connor-McCourt

  3. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Robert S. Kerbel

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  1. William Cruz-Muñoz
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  2. Teresa Di Desidero
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Correspondence to Robert S. Kerbel.

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Cruz-Muñoz, W., Di Desidero, T., Man, S. et al. Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer. Angiogenesis 17, 661–673 (2014). https://doi.org/10.1007/s10456-014-9422-9

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