Combined treatment of pancreatic cancer xenograft with (90)Y-ITGA6B4-mediated radioimmunotherapy and PI3K/mTOR inhibitor.
Combined treatment of pancreatic cancer xenograft with (90)Y-ITGA6B4-mediated radioimmunotherapy and PI3K/mTOR inhibitor.
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DOI：
10.3748/wjg.v23.i42.7551
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发表时间：
2017-11-14
影响因子：
4.3
通讯作者：
Higashi T
中科院分区：
文献类型：
--
作者：
Aung W;Tsuji AB;Sudo H;Sugyo A;Ukai Y;Kouda K;Kurosawa Y;Furukawa T;Saga T;Higashi T
研究整合素α6β4靶向放射免疫治疗（RIT）和PI 3 K/mTOR抑制剂BEZ 235联合治疗胰腺癌模型的疗效。用免疫印迹法检测90钇（90 Y）标记的抗整合素α6β4抗体（ITGA 6 B4）和BEZ 235处理的BxPC-3人胰腺癌细胞中Akt、mTOR、下游效应子真核起始因子4 E结合蛋白1（4 EBP 1）和S6核糖体蛋白（S6）的磷酸化。使用集落形成测定研究BEZ 235的细胞毒性作用。使用携带BxPC-3异种移植肿瘤的小鼠评估口服BEZ 235施用的治疗功效增强。对肿瘤进行肿瘤体积测量和免疫组织化学分析（细胞增殖标志物Ki-67、DNA损伤标志物p-H2 AX和p-4 EBP 1染色），以评价90 Y-ITGA 6 B4加BEZ 235的联合治疗或每组单独治疗。我们发现BEZ 235抑制Akt（p-Akt）、4 EBP 1（p-4 EBP 1）和S6（p-S6）的磷酸化。BxPC-3细胞中的集落形成被90 Y-ITGA 6 B4和BEZ 235的组合相加抑制。在90 Y-ITGA 6 B4暴露前用BEZ 235预处理导致细胞接种效率（PE）显著降低185 kBq/mL 90 Y-ITGA 6 B4照射组为0.54 ± 0.11，对照组为2.81 ± 0.14，P < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09（370 kBq/mL 90 Y-ITGA 6 B4暴露），P < 0.01）。在体内，与90 Y-ITGA 6 B4单次注射治疗相比，90 Y-ITGA 6 B4 + BEZ 235联合治疗增强了对肿瘤生长的抑制，并且在治疗开始日期后27天观察到相对肿瘤体积的统计学显著差异（第27天为1.03 ± 0.38 vs 1.5 ± 0.15，P < 0.05），与BEZ 235单独治疗相比（第41天为1.8 ± 0.7 vs 3.14 ± 1.19，P < 0.05）持续41天。治疗组的肿瘤体积缩小，Ki-67阳性细胞减少，p-H2 AX阳性细胞增加，p-4 EBP 1表达减少。在胰腺癌模型中，90 Y-ITGA 6 B4-RIT可以通过与双重PI 3 K和mTOR抑制剂BEZ 235组合来改善治疗功效，这表明潜在的临床应用。
To investigate the therapeutic effect of combined integrin α6β4-targeted radioimmunotherapy (RIT) and PI3K/mTOR inhibitor BEZ235 in a pancreatic cancer model. Phosphorylation of Akt, mTOR, the downstream effectors eukaryotic initiation factor 4E binding protein 1 (4EBP1) and S6 ribosomal protein (S6) were evaluated in BxPC-3 human pancreatic cancer cells treated with Yttrium-90 (90Y) labeled anti-integrin α6β4 antibody (ITGA6B4) and BEZ235 by western blotting. The cytotoxic effect of BEZ235 was investigated using a colony formation assay. Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing BxPC-3 xenograft tumors. Tumor volume measurements and immunohistochemical analyses (cell proliferation marker Ki-67, DNA damage marker p-H2AX and p-4EBP1 staining) of tumors were performed for evaluation of combined treatment with 90Y-ITGA6B4 plus BEZ235, or each arm alone. We found that phosphorylation of Akt (p-Akt), 4EBP1 (p-4EBP1) and S6 (p-S6) was inhibited by BEZ235. Colony formation in BxPC-3 cells was additively suppressed by the combination of 90Y-ITGA6B4 and BEZ235. Pretreatment with BEZ235 before 90Y-ITGA6B4 exposure resulted in significant reduction of cells plating efficiency (PE) (0.54 ± 0.11 vs 2.81 ± 0.14 with 185 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09 with 370 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01) when 5 × 103 cells per dish were plated. In vivo, the combined treatment with 90Y-ITGA6B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the 90Y-ITGA6B4 single injection treatment (1.03 ± 0.38 vs 1.5 ± 0.15 at Day 27, P < 0.05), and for 41 d when compared with the BEZ235 treatment alone (1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P < 0.05). Tumors from treatment groups showed reduction in volumes, decreased Ki-67-positive cells, increased p-H2AX-positive cells and decreased p-4EBP1 expression. The therapeutic efficacy of 90Y-ITGA6B4-RIT can be improved by combining with dual PI3K and mTOR inhibitor, BEZ235, in a pancreatic cancer model suggesting potential clinical application.
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影响因子：
8.8
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
通讯作者：
Hedley, D. W.
DOI：
10.1158/1078-0432.ccr-13-1607
发表时间：
2014-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gil del Alcazar CR;Hardebeck MC;Mukherjee B;Tomimatsu N;Gao X;Yan J;Xie XJ;Bachoo R;Li L;Habib AA;Burma S
通讯作者：
Burma S
影响因子：
5.7
作者：
Potiron, Vincent A.;Abderrhamani, Rym;Supiot, Stephane
通讯作者：
Supiot, Stephane
影响因子：
9
作者：
Chang, L.;Graham, P. H.;Hao, J.;Ni, J.;Bucci, J.;Cozzi, P. J.;Kearsley, J. H.;Li, Y.
通讯作者：
Li, Y.
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos