Fig. 7: CX-5461 shows promising anti-tumor activity in combination with TOP1 inhibitors in vivo using orthotopic PDX mouse models.
a Quantification of RADAR assay for TOP2-DNA adduct formation in SJNBL046 PDXs harvested from CX-5461 treated mice or control. Tissues were obtained from our placebo and CX-5461 group in Fig. 7m. Data represent the mean ± SD of 12 replicates. b Western blots for γ-H2AX in tumor tissue obtained during PK study. Mice were treated with 25 mg/kg CX-5461 by IP injection and tumors harvested at 1 h or 24 h. β-Actin was used as a loading control. c RT-qPCR for 45s rRNA in the same tissue as Fig. 7A. Data represent the mean ± SD of 12 replicates. n.s. no significant difference. d Genome-wide gene expression as measured by RNA-seq in MYCN amplified patient tumor SJNBL046 and in the PDX derived from this tumor. TOP2B is highlighted. e Same as (d) but showing data from the ATRX mutant sample SJNBL047443. Representative image from tumor monitoring using luciferase bioluminescence imaging (f) and ultrasound (g). h Drug combination schedule depicted for a single cycle in study 1. Mice were treated for four cycles. i Change of bodyweight (% of week 1) for each group of mice at the end of therapy or at death (the mice that died before the completion of therapy) in study 1 (described in (h)). Each datapoint represents a mouse. Data represent the mean ± SD. P-values (left to right): SJNB046, 9.2 × 10−3, 2.4 × 10−3, 7.4 × 10−3, 0.043, 0.29, 0.078, 2.3 × 10−4; SJNB047443, 0.11, 0.027, 0.88, 3.4 × 10−3, 0.036, 0.15, 0.030. j Kaplan−Meier curves showing the proportion of mice alive in each treatment group with a tumor burden estimated at <20% of bodyweight in study 1 (described in (h)). The number of mice censored in each treatment group at each time point is shown below. P-values were calculated between pairs of curves using a log-rank test and are depicted by a vertical line, with the number of dots corresponding to the level of significance; comparisons yielding P > 0.05 are not shown. k Drug combination schedule depicted for a single cycle in study 2. Mice were treated for four cycles. l Like (i) but showing bodyweights for study 2 (described in (k)). Each datapoint represents a mouse. Data represent the mean ± SD. P-values (left to right): SJNB046, 0.020, 2.3 × 10−3, 0.11, 0.99, 0.44, 0.44; SJNB047443, 1.2 × 10−3, 1.3 × 10−5, 0.020, 0.80, 0.73, 0.65. m Like (j) but showing the results of study 2 (described in (k)). Two-tailed t-test was used for (a, c, i, l). Source data for a, c, i, j, l, and m are included in Source Data file.
