Fig 1: VXL and IACS-010759 induce profound metabolic damage in vivo and leads to improvement of tumor burden reduction and overall survival in PDX models in vivo.a MS Heatmap of metabolites in BM of mice transplanted with NOTCH1-mutated PDX80 after 12 h of treatment with vehicle, IACS-010759, VXL, or the combination of IACS-010759 and VXL (n = 2). b CyTOF heatmap of spleen samples from PDX80 model treated with vehicle, IACS-010759, VXL, or the combination of IACS-010759 and VXL (n = 2). c CyTOF UMAP for CD45, CD3, CD5, CD7 and Ki67 markers in spleen samples from PDX80 model treated with vehicle, IACS-010759, VXL, or the combination of IACS-010759 and VXL (n = 2). d Gene expression analysis of spleen samples from PDX80 model after treatment with the combination of IACS-010759 and VXL compared to vehicle treatment. e Leukemic engraftment (% of human CD45+ leukemia cells) in spleen at day 5 of treatment with vehicle, VXL, IACS-010759, or the combination of IACS-010759 and VXL, as measured by FL in 3 PDX models (from left to right: PDX D115, PDX CU76, PDX 80) (mean ± SD, n = 4 individual mice per treatment arm); one-way ANOVA; *p = 0.01; **p = 0.0016; ***p = 0.0002, ****p < 0.0001. f Tumor burden development in 3 PDX models (from left to right: PDX D115, PDX CU76, PDX 80) measured as weekly detection of circulating human CD45+ cells in peripheral blood (PB) and expressed as percent of normalized human to sum of human and murine CD45+ cells in mice undergoing treatment with vehicle, IACS-010759 (5 mg/kg once daily, 5 days on/2 days off), VXL (once weekly), or the combination of IACS-010759 and VXL (mean ± SD, n = 10 mice per treatment arm for PDX D115 and PDX CU76 and n = 8 mice per treatment arm for PDX 80). g Kaplan–Meier survival curves of mice transplanted with PDX models (from left to right: PDX D115, PDX CU76, PDX 80) and treated with vehicle, IACS-010759, VXL, or the combination of IACS-010759 and VXL (n = 8). Treatment was initiated once the level of circulating leukemia cells in PB reached 0.5–1%; the timeframe of treatment is labeled by the yellow windows on the graphs. log-rank test: ***p < 0.0006 ****p < 0.0001.