Blockade of Nonhormonal Fibroblast Growth Factors by FP-1039 Inhibits Growth of Multiple Types of Cancer
Blockade of Nonhormonal Fibroblast Growth Factors by FP-1039 Inhibits Growth of Multiple Types of Cancer
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DOI：
10.1126/scitranslmed.3005414
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发表时间：
2013-03-27
影响因子：
17.1
通讯作者：
Baker, Kevin P.
中科院分区：
文献类型：
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作者：
Harding, Thomas C.;Long, Li;Baker, Kevin P.
成纤维细胞生长因子（FGF）途径促进许多实体瘤中的肿瘤生长和血管生成。虽然人们对FGF通路抑制剂的兴趣由来已久，但其开发一直很复杂：有效的FGF抑制剂必须阻断多种促有丝分裂FGF配体的活性，但必须保留代谢激素FGF（FGF-19、FGF-21和FGF-23）以避免不可接受的毒性。为了实现这些设计要求，我们工程化了可溶性FGF受体1 Fc融合蛋白FP-1039。FP-1039与所有促有丝分裂FGF配体紧密结合，在体外抑制FGF刺激的细胞增殖，在体内阻断FGF和血管内皮生长因子（VEGF）诱导的血管生成，并在体内抑制多种肿瘤类型的生长。FP-1039抗肿瘤反应与FGF 2、FGF 18、FGFR 1c、FGFR 3c和ETV 4的RNA水平呈正相关; FGF途径中存在遗传畸变的模型，包括FGFR 1扩增的肺癌和FGFR 2突变的子宫内膜癌，对FP-1039介导的肿瘤抑制作用特别敏感。FP-1039不明显结合激素FGF，因为这些配体需要细胞表面共受体klotho或β-klotho用于高亲和力结合和信号传导。受FGF-23调节的血清钙和磷酸盐水平不会因给予FP-1039而改变。通过选择性阻断非激素FGF，FP-1039治疗赋予抗肿瘤功效，而没有与其他FGF途径抑制剂相关的毒性。
The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039-mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or beta-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.