Fig. 8: Efficacy of brain-permeable microtubule-targeting agent and LXR agonist in glioblastoma xenografts.
From: Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma
a, b Structures, efficacy (EC50; A172 cell viability) and metabolic stability (t1/2; human liver microsomes) of CMPD1, analogues 10 and 17, and WJA88. c Plasma and brain concentrations of WJA88 (50 mg/kg, i.v., n = 3 mice). d Images of NPP-tdTomato tumour sections following vehicle or WJA88 treatment (n = 5 per treatment). Tumour cells are indicated by expression of tdTomato (red), with sections stained for DAPI (grey). Representative images of 3 sections per brain are shown. Scale bar = 1000 µm. e Ki67 immunostaining of WJA88 and vehicle-treated NPP-tdTomato tumours. Tumour cells (red) are marked for proliferation with Ki67 (cyan). Green arrows indicate proliferative (Ki67+/tdTomato+) and white arrows indicate non-proliferative (Ki67-/tdTomato+) tumour cells. Representative images of 3 sections per brain are shown. Scale bar = 100 µm. f Quantification of proliferative (Ki67+/tdTomato+) tumour cells. Data are mean ± SD (n = 5 per treatment). Unpaired t-test with Welch’s correction: * indicates p (two tailed) = 0.0117. g Quantification of RKI1 and FPW1 drug-tolerant persister (DTP) cells surviving WJA88 (25 µM, 14 days) ± MRK-740 (3 µM) or LXR-623 (1 µM). Data are mean ± SD (n = 3 biological replicates). One sample t-test between co-treatment vs WJA88: ** indicatesp (two tailed) = 0.0054, p (two tailed) = 0.0061 for WJA88 + MRK-740 and WJA88 + LXR-623, respectively in RKI1 cells, *** indicates p (two tailed) = 0.0007, p (two tailed) = 0.0005 for WJA88 + MRK-740 and WJA88 + LXR-623, respectively in FPW1 cells. Representative images are provided in the Supplementary Fig. 8e. h, i Images and quantification of GBM6 spheroids viability when treated with WJA88 (10 or 25 μM) and LXR-623 (1 μM). Data are mean ± SD of 3 spheroids per treatment. Unpaired t-test between treatments: ** indicates p (two tailed) = 0.0019, *** indicates p (two tailed) = 0.0004. Scale bar = 100 nm. j Bioluminescence of GBM6 orthotopic tumours in mice treated with WJA88 (50 mg/kg) ± LXR-623 (100 mg/kg). Boxplots show mean (middle line) ± SD, whiskers represent minimum to maximum data points (n = 8 per treatment). Unpaired t-test between treatments: * indicates p (two tailed) = 0.0466, p (two tailed) = 0.029 for 12 and 21 days, respectively; ** indicates p (two tailed) = 0.0054. k Kaplan-Meier regression showing survival (%) in mice with GBM6 orthotopic tumours and treated with WJA88 (50 mg/kg) ± LXR-623 (100 mg/kg). Significance was determined with log rank (Mantel-Cox) test between the survival curves for vehicle vs treatment (n = 8 per treatment). l Changes in body weight of mice with GBM6 orthotopic tumours treated as in (j). Source data are provided as a Source Data file.
