AZ1366

athymic (nu⁺/nu⁺) (4-6 week old female; subcutaneous patient-derived colorectal adenocarcinoma xenografts, F1-F3 generations)^[1]

50 mg/kg (efficacy)

p.o.; 5 days;

Induced significant tumor growth reduction in 6 out of 18 colorectal cancer patient-derived xenograft models.
Reached a tumor growth inhibition index (TGII) of 10% in the CRC040 model.
Caused plasma and tumor concentrations to peak within 1 hour and become undetectable by 30 hours in PK/PD analysis of CRC040.
Elevated Axin2 protein levels as early as 15 minutes, peaked at 8 hours, then declined in CRC040.
Increased phosphorylation of CDC2 at 8 hours and cleaved caspase-3 at 48 hours in CRC040.
Did not reduce active β-catenin or c-Myc levels in CRC040, nor nuclear β-catenin levels in CRC114.
Reduced NuMA protein levels, decreased the interaction between tankyrase and NuMA, and increased phosphorylation of CDC2 and CDK2 after 7 days of treatment in combination-sensitive models (CRC026, CRC147).
Stabilized Axin2 protein levels in all evaluated models but did not reduce WNT-dependent signaling (active β-catenin, CD44, Axin2, Jag1 gene expression).
Induced significant tumor growth reduction in 4 out of 18 irinotecan-resistant colorectal cancer patient-derived xenograft models (CRC010, CRC026, CRC114, CRC147) with elevated baseline tankyrase and NuMA levels.
Stabilized Axin2 protein levels, reduced NuMA protein levels, decreased the interaction between tankyrase and NuMA, and increased phosphorylation of CDC2 and CDK2 in combination-sensitive models.
Did not reduce WNT-dependent signaling (active β-catenin, CD44, Axin2, Jag1 gene expression).

Athymic nude mice (8-12 week old female; orthotopically implanted luciferase-tagged HCC4006 NSCLC cells, randomized when tumor reached 5×10⁸ p/s) (orthotopically implanted luciferase-tagged H1650 NSCLC cells, randomized when tumor reached 5×10⁸ p/s)^[2]

25 mg/kg (combination with gefitinib; survival, tumor growth); 50 mg/kg (combination with gefitinib; no survival benefit); 25 mg/kg (single agent; no survival benefit)

p.o.; daily for 5 days per week

Did not significantly change tumor burden at death or increase median survival as single agent.
Increased median survival from 92 days (gefitinib alone) to 152 days, significantly increased tumor doubling time, and slowed tumor growth when co-administered with gefitinib at 25 mg/kg.
Did not provide similar survival advantage when co-administered with gefitinib at 50 mg/kg.
Stabilized intratumoral Axin-1 at 24 and 72 hours post single-dose administration, with stabilization sustained through 72 hours but lost by 168 hours.
Did not significantly change tumor burden at death or increase median survival (41 days vs.
55 days for vehicle) as single agent.
Increased median survival from 59 days (gefitinib alone) to 168 days, significantly increased tumor doubling time, and slowed tumor growth when co-administered with gefitinib at 25 mg/kg.
Did not provide similar survival advantage when co-administered with gefitinib at 50 mg/kg.