Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models
Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models
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DOI：
10.18632/oncotarget.9029
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发表时间：
2016-07-26
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影响因子：
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通讯作者：
Schwarz, Roderich E.
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文献类型：
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作者：
Awasthi, Niranjan;Scire, Emily;Schwarz, Roderich E.
NAB-紫杉醇最近在治疗胰腺导管腺癌(PDAC)方面显示出更好的疗效。胰岛素样生长因子(IGF)信号蛋白在PDAC中经常过表达，并与侵袭性肿瘤表型和不良预后相关。我们评估了在临床前PDAC模型中加入胰岛素样生长因子-1R/IR信号的小分子抑制剂BMS-754807对NAB-紫杉醇反应的改善。在使用AsPC-1细胞的异种皮下移植瘤中，不同治疗组的肿瘤平均净生长分别为对照组248.3 mm(3)、NaB-紫杉醇+BMS-754807组93.3 mm(P=0.002)和NaB-紫杉醇+BMS-0.0002组(P=0.0002)。在使用PANC-1细胞的皮下移植瘤中，不同治疗组的平均肿瘤净生长分别为：对照组294.3 mm(3)，NaB-紫杉醇+BMS-754807组23.1 mm(3)，BMS-754807组118.2 mm(3)(p=0.002)，肿瘤消退-87.4 mm(3)(p=0.0001)。在使用AsPC-1细胞的腹膜转移模型中，NaB-紫杉醇(40天，增加90%，p=0.002)、bms-754807(27天，增加29%，p=0.002)和NaB-紫杉醇+bms-754807(47天，增加124%，p=0.005)组动物的中位生存期比对照组(21天)增加。NaB-紫杉醇和BMS-754807抑制肿瘤细胞增殖、促进细胞凋亡与其体内抗肿瘤活性有关。体外分析表明，加入IC25剂量的BMS-754807可降低pDAC细胞株对NaB-紫杉醇的IC50。BMS-754807治疗降低了磷酸化IGF1R/IR和磷酸化AKT的表达，增加了caspase-3和PARP-1的裂解。这些结果支持BMS-754807联合NaB-紫杉醇作为胰腺癌治疗的有效靶向选择的潜力。
Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm(3) in controls, 42.4 mm(3) after nab-paclitaxel (p = 0.002), 93.3 mm(3) after BMS-754807 (p = 0.01) and 1.9 mm(3) after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm(3) in controls, 23.1 mm(3) after nab-paclitaxel (p = 0.002), 118.2 mm(3) after BMS-754807 (p = 0.02) and -87.4 mm(3) (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.