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

Peter J. Houghton, Raushan T. Kurmasheva, Dmitry Lyalin, John M. Maris, E. Anders Kolb, Richard Gorlick, C. Patrick Reynolds, Min H. Kang, Stephen T. Keir, Jianrong Wu, Malcolm A. Smith

Research output: Contribution to journalArticle

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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 1.0nM to 10μM and against the PPTP in vivo solid tumor xenograft panels at (60mg/kg once daily (SID)×5) for three consecutive weeks. Additional studies evaluated 5 to 20mg/kg BID×5 with SID dosing at 7-30mg/kg at weekends for three consecutive weeks. Results: In vitro the median relative IC<inf>50</inf> (rIC<inf>50</inf>) for the PPTP cell lines was 1.5μM, with a range from 0.3μM to 5.9μM. The two cell lines with rIC<inf>50</inf> values of 0.3μM 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.

Original languageEnglish (US)
Pages (from-to)1972-1979
Number of pages8
JournalPediatric Blood and Cancer
Volume61
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Janus Kinase 1
Janus Kinase 2
Pediatrics
Heterografts
Neoplasms
Sudden Infant Death
Wilms Tumor
Cell Line
Inhibitory Concentration 50
Growth
Angiogenesis Inhibitors
AZD 1480
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adenosine Triphosphate
Phosphorylation

Keywords

  • Developmental therapeutics
  • JAK1/2 inhibitor
  • Preclinical testing

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Houghton, P. J., Kurmasheva, R. T., Lyalin, D., Maris, J. M., Kolb, E. A., Gorlick, R., ... Smith, M. A. (2014). Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 61(11), 1972-1979. https://doi.org/10.1002/pbc.25175

Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program. / Houghton, Peter J.; Kurmasheva, Raushan T.; Lyalin, Dmitry; Maris, John M.; Kolb, E. Anders; Gorlick, Richard; Reynolds, C. Patrick; Kang, Min H.; Keir, Stephen T.; Wu, Jianrong; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 61, No. 11, 01.11.2014, p. 1972-1979.

Research output: Contribution to journalArticle

Houghton, PJ, Kurmasheva, RT, Lyalin, D, Maris, JM, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Keir, ST, Wu, J & Smith, MA 2014, 'Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 61, no. 11, pp. 1972-1979. https://doi.org/10.1002/pbc.25175
Houghton, Peter J. ; Kurmasheva, Raushan T. ; Lyalin, Dmitry ; Maris, John M. ; Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Keir, Stephen T. ; Wu, Jianrong ; Smith, Malcolm A. / Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2014 ; Vol. 61, No. 11. pp. 1972-1979.
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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 1.0nM to 10μM and against the PPTP in vivo solid tumor xenograft panels at (60mg/kg once daily (SID)×5) for three consecutive weeks. Additional studies evaluated 5 to 20mg/kg BID×5 with SID dosing at 7-30mg/kg at weekends for three consecutive weeks. Results: In vitro the median relative IC50 (rIC50) for the PPTP cell lines was 1.5μM, with a range from 0.3μM to 5.9μM. The two cell lines with rIC50 values of 0.3μM 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.",
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AU - Lyalin, Dmitry

AU - Maris, John M.

AU - Kolb, E. Anders

AU - Gorlick, Richard

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Keir, Stephen T.

AU - Wu, Jianrong

AU - Smith, Malcolm A.

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AB - 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 1.0nM to 10μM and against the PPTP in vivo solid tumor xenograft panels at (60mg/kg once daily (SID)×5) for three consecutive weeks. Additional studies evaluated 5 to 20mg/kg BID×5 with SID dosing at 7-30mg/kg at weekends for three consecutive weeks. Results: In vitro the median relative IC50 (rIC50) for the PPTP cell lines was 1.5μM, with a range from 0.3μM to 5.9μM. The two cell lines with rIC50 values of 0.3μM 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.

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