Fig. 6: The anti-depressant vortioxetine confers significant survival benefit across preclinical trials and synergizes with standard-of-care glioblastoma treatments.
a, scRNA-seq expression of select marker genes in patient sample P024. Cluster IDs are based upon UMAP clusters in Extended Data Fig. 9a. Black lines, median. b, Differentially expressed AP-1 TFs and effector gene ARC per scRNA-seq cluster in a, upon vortioxetine (VORT) treatment relative to DMSO. Circle sizes, −log10(adjusted P value); color scale, VORT-induced log2(fold change (FC)) compared to DMSO-treated cells per cluster. c, Example single-cell image crops from patient P040 of Nestin+ (yellow) cells after VORT treatment (+; 20 µM) and DMSO at 24 h stained with different AP-1 factors (red) and DAPI (blue). Scale bar, 15 µm. d, VORT ex vivo response (x axis; PCY score) versus AP-1 induction in Nestin+ glioblastoma cells by IF (y axis; log2(fold change) in mean intensity relative to DMSO) across patient samples (n = 11) at 24 h after VORT treatment (10 µM and 20 µM; VORT conc.). Pearson’s linear correlation coefficients and two-tailed P values are indicated. e, Survival analysis across three independent in vivo trials—Trial I: LN-229, Trial II: ZH-161 and Trial III: ZH-161—each with n = 6–7 tumor-bearing mice per treatment group and n = 7 treatments per trial. Doses are denoted in parentheses, and * indicates drugs used in a subset of the three trials. f, Survival analysis of in vivo Trial IV: ZH-161-iRFP720 tumor-bearing mice (n = 6 mice per treatment group). g, Representative MRI images of ZH-161-iRFP720 transplanted mice (columns; Trial IV; n = 4 mice) 38 d after tumor implantation (n = 3 drugs) with tumor perimeters indicated (yellow). h, Tumor perimeters of drug-treated mice in g, at multiple timepoints after tumor implantation by MRI. One-way ANOVA with adjusted P value from Tukey’s multiple comparisons test at day 38. i, Survival analysis of in vivo Trial V: ZH-161 tumor-bearing mice (n = 5–6 mice per group). j, Preclinical evidence for the top PCY-hit NAD VORT across modalities. AP-1 Val., AP-1 validation samples (n = 10 and n = 1 overlap with COSTAR); COSTAR, COSTAR validation samples (n = 4); Pros. GBM, prospective patient cohort (n = 27). *, among tested drugs and timepoints. e,f,h, Survival plotted as Kaplan–Meier curves and P values (colored by drug) calculated using log-rank (Mantel–Cox) test. Censored mice are denoted as tick marks. PCY-HIT, PCY-hit.
