Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617; Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Cancer Lett. 2015 Mar 1;358(1):59-66. doi: 10.1016/j.canlet.2014.12.027. Epub 2014 Dec 16.
Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma (PDAC) therapy. VEGF, PDGF, FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC. Nintedanib is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β signaling. We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC. Nintedanib inhibited proliferation of cells from multiple lineages found in PDAC, with gemcitabine enhancing inhibitory effects. Nintedanib blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo. In a heterotopic model, net local tumor growth compared to controls (100%) was 60.8 ± 10.5% in the gemcitabine group, -2.1 ± 9.9% after nintedanib therapy and -12.4 ± 16% after gemcitabine plus nintedanib therapy. Effects of therapy on intratumoral proliferation, microvessel density and apoptosis corresponded with tumor growth inhibition data. In a PDAC survival model, median animal survival after gemcitabine, nintedanib and gemcitabine plus nintedanib was 25, 31 and 38 days, respectively, compared to 16 days in controls. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy.
血管生成仍然是胰腺导管腺癌（PDAC）治疗的一个合理靶点。VEGF、PDGF、FGF 及其受体在人类 PDAC 中高表达，并与预后不良相关。尼达尼布是一种三激酶抑制剂，可靶向 VEGFR1/2/3、FGFR1/2/3 和 PDGFRα/β 信号通路。我们研究了尼达尼布单独或联合细胞毒性药物吉西他滨在实验性 PDAC 中的抗肿瘤活性。尼达尼布抑制 PDAC 中多个谱系细胞的增殖，吉西他滨增强抑制作用。尼达尼布阻断 PI3K/MAPK 活性并诱导体外和体内细胞凋亡。在异位模型中，与对照组（100%）相比，吉西他滨组的局部肿瘤净生长为 60.8±10.5%，尼达尼布治疗组为-2.1±9.9%，吉西他滨加尼达尼布治疗组为-12.4±16%。治疗对肿瘤内增殖、微血管密度和凋亡的影响与肿瘤生长抑制数据一致。在 PDAC 生存模型中，吉西他滨、尼达尼布和吉西他滨加尼达尼布治疗后的中位动物生存时间分别为 25、31 和 38 天，而对照组为 16 天。尼达尼布在实验性 PDAC 中的强烈抗肿瘤活性支持将尼达尼布控制的机制作为改善临床 PDAC 治疗的靶点的潜力。
