Fig. 2: Irinotecan in combination with PEV exhibits synergy in preclinical CRC models.

a Top panels: Three 3D organoids generated from liver-dominant metastatic CRC patients (mCRC PDOs #1, #2 and #3) were treated with SN38 plus PEV as indicated for 72 h for CellTiter-Glo Luminescent Cell Viability Assay (mean ± SD, N = 3 biologically independent experiments). Bottom panels: SN38-PEV pairs ranked by ExcessHSA metric using Combenefit. b Brightfield images of mCRC PDO #1 treated with mock (no treatment), 2.5 µM PEV, 1.25 µM SN38 or 2.5 µM PEV + 1.25 µM SN38. The scale bar represents 50 µm. c HCT116 tumor-bearing athymic nude mice were treated either with vehicle, PEV (2.5 mg/kg), irinotecan (20 mg/kg) or a combination of PEV plus irinotecan. Treatments were initiated 10 days after tumor inoculation when mean tumor size reached 95.7 mm³. Tumor growth is shown as fold-change versus first day of treatment (n = 10 per treatment group, except n = 8 for PEV 2.5 mg/kg). d Kaplan–Meier survival curve of mice following the three treatment cycles (n = 10 in vehicle and PEV group, n = 7 all other groups). Survival after treatment with low dose PEV (2.5 mg/kg) in combination with irinotecan. p value determined by Mantel–Cox test. e Kaplan–Meier survival curve of mice following the three treatment cycles (n = 10 in vehicle and PEV group, n = 7 all other groups). Survival after treatment with high dose (15 mg/kg) in combination with irinotecan. p value determined by Mantel–Cox test. f Left panel: representative bioluminescence images 21 days after treatment start; Right panel: Quantification of bioluminescence imaging (n = 10 per treatment group, except n = 8 for PEV 2.5 mg/kg). Data are shown as mean ± SEM. p values determined by two-tailed Student’s t test.