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Initial solid tumor testing (stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical
Peter J Houghton1, Raushan T Kurmasheva, Dmitry Lyalin
1Nationwide Children's Hospital, Columbus, Ohio.
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 microM and against the PPTP in vivo solid tumor xenograft panels at (60 mg/kg once daily (SID) × 5) for three consecutive weeks. Additional studies evaluated 5 to 20 mg/kg BID × 5 with SID dosing at 7-30 mg/kg at weekends for three 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 three of six 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.
Insights
AZD1480, a Janus kinase inhibitor, significantly inhibited solid tumor growth in preclinical models. The drug showed notable tumor regression in Wilms tumor xenografts, highlighting its therapeutic potential.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- AZD1480 is an ATP-competitive inhibitor targeting Janus kinases 1 and 2 (JAK1, 2).
- It has demonstrated efficacy in inhibiting solid tumor growth in preclinical models.
- This study investigated the role of JAK/STAT signaling in standard PPTP solid tumor models using AZD1480.
Purpose of the Study:
- To evaluate the efficacy of AZD1480 in inhibiting the growth of solid tumors.
- To assess the role of JAK/STAT signaling in PPTP solid tumor models.
- To determine tumor regression activity of AZD1480 in specific xenograft models.
Main Methods:
- AZD1480 was tested in vitro against a panel of PPTP cell lines (1.0 nM to 10 microM).
- In vivo studies utilized PPTP solid tumor xenograft panels with various dosing regimens (e.g., 60 mg/kg SID × 5).
- Inhibition of Stat3(Y705) phosphorylation was assessed in relation to tumor regression.
Main Results:
- In vitro, the median relative IC50 was 1.5 µM, with lower values in cell lines harboring ALK alterations.
- AZD1480 showed statistically significant differences in event-free survival (EFS) compared to control in 89% of xenografts.
- Significant growth inhibition (intermediate or high) was observed in 50% of xenografts, with tumor regressions in Wilms tumor models.
Conclusions:
- AZD1480 demonstrated substantial tumor growth inhibition across most PPTP solid tumor xenografts.
- The drug's activity was comparable to known antiangiogenic agents.
- Tumor-regressing effects were specifically noted in Wilms tumor xenografts.