Research ArticleCancer

Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ra50
DOI: 10.1126/scitranslmed.3010722

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A treatment a day keeps metastasis away

Renal cancer is usually thought to be resistant to standard chemotherapy, and even modern targeted drugs are only temporarily effective because the tumors develop resistance to treatment. Now, Jedeszko et al. used realistic mouse models to show that some of these treatments may offer more hope than previously thought. To mimic the clinical situation, the authors allowed tumors to develop in the kidneys of their mouse models, surgically removed them, and started chemotherapy as one would for human patients. In this setting, the authors showed that daily treatments with low-dose topotecan, a chemotherapy drug, were effective when combined with pazopanib, an antiangiogenic agent, and the combination could treat both primary and metastatic renal cancers.


Renal cell carcinoma (RCC), normally considered an intrinsically chemotherapy-resistant cancer, is currently treated with targeted biologic therapies, including antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib. The efficacy of these agents is limited by both intrinsic and acquired resistance. Death is almost always due to advanced metastatic disease, a treatment circumstance seldom modeled in preclinical (mouse) drug testing. Similarly, therapy results using postsurgical adjuvant therapy models of microscopic disease have not been reported. Using in vivo selection and transfection of established human RCC cell lines (786-0 and SN12-PM6), we derived clonal luciferase-expressing variants capable of spontaneous metastasis from an orthotopic primary tumor to organs typical of clinical RCC, including bone, lungs, and brain. The bioluminescence and consistent metastatic spread of von Hippel–Lindau–wild type SN12-PM6-1 cells allowed for the establishment of perioperative therapy models of RCC. We report that the combination of daily low-dose metronomic topotecan with pazopanib has highly potent antiprimary tumor as well as both postsurgical adjuvant and metastatic therapy efficacy despite lack of an antimetastatic effect of pazopanib monotherapy. The combination therapy resulted in sustained metastatic tumor cell dormancy, but tumor progression occurred upon treatment cessation. We also obtained evidence for a direct effect of pazopanib on RCC cells, resulting in increased intracellular concentration of topotecan. Our results suggest that this type of treatment combination should be considered for clinical evaluation in early- or late-stage metastatic disease, even for tumors seemingly intrinsically “resistant” to antiangiogenic TKIs or chemotherapy.

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