er-086526 and Wilms-Tumor

Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor.. Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to 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. 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 activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24 hours only after treatment with the eribulin combination.. The eribulin combination is very active in these xenograft models, but not synergistic

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Female; Furans; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Ketones; Kidney Neoplasms; Mice; Mice, SCID; Prognosis; Rhabdomyosarcoma; Tumor Cells, Cultured; Vincristine; Wilms Tumor; Xenograft Model Antitumor Assays