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Combination therapy with AG-490 and interleukin 12 achieves greater antitumor effects than either agent alone
Lyudmila Burdelya1, Robyn Catlett-Falcone, Alexander Levitzki
1Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Abstract:
Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) occurs at very high frequency in various hematopoietic malignancies and solid tumors. It has been demonstrated that the tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely eliminates leukemia cells in a severe combined immunodeficient (SCID) mouse model. Because many cytokines, including interleukin (IL)-12, have been shown to signal through JAK/STAT pathways, AG-490 may inhibit cytokine-based cancer therapy. In this study, we evaluated the effects of AG-490 on IL-12 functional signaling and IL-12-mediated antitumor response in vivo. Previous studies have established the critical roles of macrophages and IFN-gamma in mediating IL-12-induced antitumor effects. Our results show that in vivo administration of AG-490 causes tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-gamma production by lymphocytes. Furthermore, our data indicate that combined therapy with AG-490 and IL-12-induces greater antitumor effects than either agent alone in a murine myeloma tumor model. These results suggest that JAK/STAT inhibitors deserve further investigation for use with IL-12 therapy in treating human cancers with elevated JAK/STAT activity.
Insights
The tyrosine kinase inhibitor AG-490 shows promise in cancer therapy. Combined with interleukin-12 (IL-12), it enhances antitumor effects, suggesting a new therapeutic strategy for cancers with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) is frequent in cancers.
- The JAK/STAT pathway is crucial for cytokine signaling, including interleukin-12 (IL-12).
- The JAK inhibitor AG-490 has shown efficacy against leukemia in preclinical models.
Purpose of the Study:
- To investigate the effects of AG-490 on IL-12 signaling and IL-12-mediated antitumor responses in vivo.
- To determine if AG-490 interferes with IL-12's established roles in macrophage activation and IFN-gamma production.
- To evaluate the combined therapeutic potential of AG-490 and IL-12 in a murine cancer model.
Main Methods:
- Administration of AG-490 and/or IL-12 to a murine myeloma tumor model.
- Assessment of tumor cell apoptosis, macrophage activation, and IFN-gamma production.
- Evaluation of in vivo antitumor efficacy of single-agent and combination therapies.
Main Results:
- AG-490 induced tumor cell apoptosis in vivo.
- AG-490 did not inhibit IL-12-mediated macrophage activation or lymphocyte IFN-gamma production.
- Combination therapy with AG-490 and IL-12 demonstrated superior antitumor effects compared to either agent alone.
Conclusions:
- JAK/STAT inhibitors like AG-490 can be combined with IL-12 therapy.
- This combination strategy shows potential for treating human cancers with elevated JAK/STAT activity.
- Further investigation of JAK/STAT inhibitors in conjunction with IL-12 therapy is warranted.