Home Blog of Signal Transduction Protein Tyrosine Kinase CSF-1R Sulfatinib, a novel multi-targeted tyrosine kinase inhibitor of FGFR1, CSF1R, and VEGFR1-3, suppresses osteosarcoma proliferation and invasion via dual role in tumor cells and tumor microenvironment

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Sulfatinib, a novel multi-targeted tyrosine kinase inhibitor of FGFR1, CSF1R, and VEGFR1-3, suppresses osteosarcoma proliferation and invasion via dual role in tumor cells and tumor microenvironment

Introduction: Tumor progression is driven by intrinsic malignant behaviors caused by gene mutation or epigenetic modulation, as well as crosstalk with the components in the tumor microenvironment (TME). Considering the current understanding of the tumor microenvironment, targeting the immunomodulatory stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) could provide a potential therapeutic strategy. Here, we investigated the effect of sulfatinib, a multi-targeted tyrosine kinase inhibitor (TKI) of FGFR1, CSF1R, and VEGFR1-3, on the treatment of osteosarcoma (OS).

Methods: In vitro, the antitumor effect was tested by clony formation assay and apoptosis assay.The inhibition of tumor migration and invasion was detected by Transwell assay, and the de-polarization of macrophage was detected by flow cytometry.In vivo, subcutaneous and orthotopic tumor models were established to verify antitumor effect, and the underlying mechanism was verified by immunohistochemistry(IHC), immunofluorescence(IF) and flow cytometry.

Results: Sulfatinib suppressed OS cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) by blocking the secretion of basic fibroblast growth factor (bFGF) in an autocrine manner. In addition, it regulated immune TME via inhibition of the migration of skeletal stem cells (SSCs) to the TME and the differentiation from SSCs to CAFs. Moreover, sulfatinib can suppress OS by modulation of the TME by inhibiting M2 polarization of macrophages. Systemic treatment of sulfatinib can reduce immunosuppression cells M2-TAMs, Tregs, and myeloid-derived suppressor cells (MDSCs) and increase cytotoxic T-cell infiltration in tumors, the lungs, and the spleens.

Discussion: Our preclinical experiments have shown that sulfatinib can inhibit the proliferation, migration, and invasion of OS by playing a dual role on tumor cells and the tumor microenvironment simultaneously and systematically reverse immunosuppression to immune activation status, which could be translated into clinical trials.

 

Comments:

This abstract highlights a comprehensive study on sulfatinib's impact on osteosarcoma (OS) treatment, delving into its effects on tumor cells and the tumor microenvironment (TME). Here's a more simplified breakdown:

**Introduction:** Tumor progression involves genetic mutations, epigenetic changes, and interactions with the TME. Targeting specific stromal cells in the TME, like cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), could be a promising therapeutic strategy.

**Methods:** The study used various in vitro and in vivo techniques to evaluate sulfatinib's impact on OS. In vitro tests involved assessing its effect on tumor growth, migration, invasion, and its influence on macrophage behavior. In vivo models, both subcutaneous and orthotopic, were employed to verify its effectiveness. Immunohistochemistry, immunofluorescence, and flow cytometry were used to understand the underlying mechanisms.

**Results:** Sulfatinib was found to hinder OS cell migration and invasion by blocking the secretion of basic fibroblast growth factor (bFGF), thus inhibiting epithelial-mesenchymal transition (EMT). Additionally, it regulated the TME by impeding the migration of skeletal stem cells (SSCs) and their differentiation into CAFs. Sulfatinib also affected the TME by preventing M2 polarization of macrophages. Its systemic treatment reduced immunosuppressive cells (M2-TAMs, Tregs, MDSCs) and increased infiltration of cytotoxic T-cells in tumors, lungs, and spleens.

**Discussion:** The preclinical experiments showcased that sulfatinib not only inhibited OS growth but also influenced the TME, shifting it from an immunosuppressive to an immune-activated state. This dual impact on tumor cells and the TME suggests potential for translation into clinical trials.

The study suggests that sulfatinib could be a promising candidate for further exploration in treating OS, potentially altering the TME dynamics and enhancing the body's immune response against the tumor.

Related Products

Cat.No. Product Name Information
S0487 Sulfatinib Sulfatinib is a potent and highly selective tyrosine kinase inhibitor against VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R with IC50 of 2 nM, 24 nM, 1 nM, 15 nM and 4 nM, respectively. Sulfatinib shows encouraging antitumor activity and manageable toxicities in patients with advanced NETs.

Related Targets

VEGFR CSF-1R FGFR