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Abstract
Purpose: Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in the treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor.
Experimental Design: Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to the event were used to assess antitumor activity. Pharmacodynamic studies and RNA sequencing (RNA-seq) were conducted 24 and 144 hours after single-agent or combination treatment. Effects on vascular development were studied in Matrigel plugs implanted in mice. The interaction between binary combinations was examined in vitro.
Results: Eribulin combined with irinotecan was more effective than vincristine–irinotecan in 6 of 12 models. Pharmacodynamic markers induced by eribulin (phospho-histone H3) and irinotecan (γ-H2A.X) were abrogated in combination-treated tumors. The predominant RNA-seq signature in combination-treated tumors was an activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24 hours only after treatment with the eribulin combination. In vitro, neither combination showed interaction using combination index analysis. Eribulin alone and the combination caused alterations in developing vasculature.
Conclusions: The eribulin combination is very active in these xenograft models, but not synergistic in vitro. The combination reduced pharmacodynamic markers indicative of single-agent mechanisms but in tumors, dramatically activated the TP53 pathway. Although a mechanism for in vivo synergy requires further study, it is possible that eribulin-induced inhibition of microtubule dynamics enhances the irinotecan-induced nuclear accumulation of TP53, leading to rapid cell death.
Translational Relevance: Topoisomerase I poisons and microtubule-targeting agents, such as vincristine, are two of the most effective classes of chemotherapeutic agents used for the treatment of pediatric cancers. Recently, the microtubule inhibitor eribulin was approved for the third-line treatment of breast cancer and liposarcoma. However, the efficacy of eribulin against pediatric solid tumors has not been thoroughly studied in the clinic. In this study, we evaluated the efficacy and mechanisms of action of eribulin and vincristine, alone and in combination with irinotecan, in preclinical xenograft models of pediatric solid tumors. Collectively, these studies provide a rationale for further evaluation of eribulin alone, and eribulin combined with irinotecan for the treatment of pediatric solid tumors that are wild type for TP53.
