Abstract 4187: Preclinical evaluation of sulfatinib, a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF1R kinases
Authors: Zhou jinghong , Ni Jun , Cheng Min , Yang Na , Liang Junqing , Ge Liang , Zhang Wei , Tang Jianxing , Sun qiaoling , Li Fu , Hu Jia , Shi Dongxia , Chen Hongbo , Long Jingwen , Sun Junen , Yin Fang , Ge Xuelei , Jia Hong , Zhou Feng , ren Yongxin , Qing Weiguo , Su Weiguo 
Published: July 2017

Abstract
Both vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) singling pathways can mediate tumor angiogenesis. Colony stimulating factor 1 receptor (CSF1R) plays an important role on functions of macrophages. Recently the roles of the VEGFR, FGFR and CSF1R in regulation of T cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells, thereby increasing tumor immune evasion, have been demonstrated[1-3]. Therefore, blockade of tumor angiogenesis and tumor immune evasion by simultaneously targeting VEGFR, FGFR and CSF1R kinases may represent a promising approach for anti-cancer therapy. We report here the preclinical studies for sulfatinib (HMPL-012), a potent and highly selective small molecule tyrosine kinase inhibitor against VEGFR, FGFR1 and CSF1R. Sulfatinib inhibited VEGFR1, 2, and 3, FGFR1 and CSF1R kinases with IC50s in a range of 1~24 nM, and it strongly blocked VEGF induced VEGFR2 phosphorylation in HEK293KDR cells and CSF1 stimulated CSF1R phosphorylation in RAW264.7 cells with IC50 of 2 and 79 nM, respectively. Sulfatinib also attenuated VEGF or FGF stimulated HUVEC cells proliferation with IC50 &lt; 50 nM. In animal studies, a single oral dosing of sulfatinib inhibited VEGF stimulated VEGFR2 phosphorylation in lung tissues of nude mice in an exposure-dependent manner. Furthermore, elevation of FGF23 levels in plasma 24 hours post dosing suggested suppression of FGFR signaling. Sulfatinib demonstrated potent tumor growth inhibition in multiple human xenograft models and decreased CD31 expression remarkably, suggesting strong inhibition on angiogenesis through VEGFR and FGFR signaling. In a syngeneic murine colon cancer model CT-26, sulfatinib demonstrated moderate tumor growth inhibition after single agent treatment. Flow cytometry and immunohistochemistry analysis revealed an increase of CD8+ T cells and a significant reduction in TAMs, (CD163+ or F4/80+CD11b+CD45+) and CSF1R+ TAMs in tumor tissue indicating strong effect on CSF1R. Interestingly, combination of sulfatinib with a PD-L1 antibody resulted in enhanced anti-tumor effect. These results suggested that sulfatinib has a strong effect in modulating angiogenesis and cancer immunity. In summary, sulfatinib is a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF1R kinases that could simultaneously block tumor angiogenesis and immune evasion. This unique feature seems to support sulfatinib as an attractive candidate for exploration of possible combinations with checkpoint inhibitors against various cancers. Sulfatinib is currently in multiple clinical trials including two Phase III trials against neuroendocrine tumors. Reference: 1. Voron T, et al. J Exp Med. 2015; 212(2):139-48. 2. Ries CH, et al. Cancer Cell. 2014; 25(6):846-59. 3. Katoh M, et al. Int. J. of Mol Med. 2016; 38: 3-15.
Citation Format: jinghong Zhou, Jun Ni, Min Cheng, Na Yang, Junqing Liang, Liang Ge, Wei Zhang, Jianxing Tang, qiaoling Sun, Fu Li, Jia Hu, Dongxia Shi, Hongbo Chen, Jingwen Long, Junen Sun, Fang Yin, Xuelei Ge, Hong Jia, Feng Zhou, Yongxin ren, Weiguo Qing, Weiguo Su. Preclinical evaluation of sulfatinib, a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF1R kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4187. doi:10.1158/1538-7445.AM2017-4187