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Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.

ABSTRACT: STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.

SUBMITTER: Xin H

PROVIDER: S-EPMC3206173 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.

Xin Hong H Herrmann Andreas A Reckamp Karen K Zhang Wang W Pal Sumanta S Hedvat Michael M Zhang Chunyan C Liang Wei W Scuto Anna A Weng Shaobu S Morosini Deborah D Cao Zhu A ZA Zinda Michael M Figlin Robert R Huszar Dennis D Jove Richard R Yu Hua H

Cancer research 20110915 21

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD14 ...[more]

PMID: 21920898

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Project description:BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & findingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

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Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.

Publications

Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.

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