Fig. 1
Impact of dose and schedule of PI3Kδ inhibitors in CT-26 syngeneic tumors model. a Line graph shows individual tumor volumes from BALB/c mice bearing CT-26 tumors. Top panels show individual tumor volume of mice dosed from 4 days after implantation at indicated dose schedule. Bottom panels indicate animals dosed when tumors reached 0.2cm3. Full lines indicate continuous schedule and dashed lines indicate 2 days on/5 days off intermittent schedules at indicated doses of AZD8835 or PI-3065. b in vivo PK and coverage illustrating the number of hours with plasma concentration above PI3Kα (black line) or PI3Kδ (orange line) cell IC50, corrected for protein in assay and plasma protein binding. c Line graph shows mean tumor volumes from BALB/c mice bearing CT-26 tumors dosed from when tumors reached 0.2cm3 or (d) dosed 4 days after implantation treated with AZD8835 2 days on/5 days off intermittent schedule (dashed vertical lines) or PI-3065 continuous schedule (grey area) (e) Line graph represents mean tumor growth in CT-26 model in immunocompromised nude mice at same schedule. f Phosphorylation levels of AKT (S473) in CT-26 tumors treated with AZD8835 at end of study related to 1D and 1E experiments. g Line graph shows mean tumor volumes from C57/Bl6 mice bearing MC-38 mouse CRC tumor model, (h) 4 T1 breast orthotopic (OT) tumors and (i) 4 T1 breast sub-cutaneous (SC) tumors from BALB/c mice bearing, (J) bar chart representing total number of lung metastasis in 4 T1 s. c mice (n = 15 mice/group). 4 T1 tumor bearing mice were treated 4 days after cell implant with AZD8835 at 50 mg/kg twice-daily intermittent schedule for 3 cycles. Data are representative of ≥2 experiments. Statistical significance is indicated as follows: * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001