Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program

Abstract

Background AZD1480 is an ATP competitive inhibitor of Janus kinases 1 and 2 (JAK1, 2) that has been shown to inhibit the growth of solid tumor models. This agent was selected for testing the putative role of JAK/STAT signaling in the standard PPTP solid tumor models. Procedures AZD1480 was tested against the PPTP in vitro cell line panel at concentrations from 1.0 nM to 10 M and against the PPTP in vivo solid tumor xenograft panels at (60 mg/kg once daily (SID) × 5) for 3 consecutive weeks. Additional studies evaluated 5 to 20 mg/kg BID × 5 with SID dosing at 7–30 mg/kg at weekends for 3 consecutive weeks. Results In vitro the median relative IC50 (rIC50) for the PPTP cell lines was 1.5 µM, with a range from 0.3 µM to 5.9 µM. The two cell lines with rIC50 values of 0.3 µM both had ALK activating genomic alterations. AZD1480 demonstrated statistically significant differences (p<0.05) in EFS distribution compared to control in 89% of the solid tumor xenografts. AZD1480 induced intermediate (EFS T/C > 2) or high-level growth inhibition in 15 of 30 (50%) solid tumor xenografts. Tumor regressions were observed in 3 of 6 Wilms tumor models at doses that induced inhibition of Stat3(Y705) phosphorylation. Conclusions AZD1480 demonstrated significant tumor growth inhibition against most PPTP solid tumor xenografts, similar to that observed for antiangiogenic agents tested by the PPTP. Tumor regressing activity was noted for Wilms tumor xenografts.

Transcriptome Variability in Keratocystic Odontogenic Tumor Suggests Distinct Molecular Subtypes

“…In addition, the oKC subtype showed activation of numerous Cellular growth, proliferation and apoptosis pathways that were not seen in the sKC subtype including the JAK/STAT pathway. Recently, a trial targeted this pathway in solid tumors with good results 24 which could be explored as an adjunctive therapy before surgery to reduce the size of the tumors and thus extent of resection and reconstruction needed to reduce the high recurrence rate of KCOT.…”

The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma

“…Although the JAK inhibitor AZD1480 did increase viability, this compound has known off-target activity against ALK itself. 28 Since no other JAK/STAT inhibitor produced any effect, we conclude the effect of this drug was due to off-target ALK inhibition. Results for additional TKI-addicted resistant lines were similar (Figure 2e, Supplementary Figure 2d, not all drugs were tested in all lines).…”