@article{oai:repo.qst.go.jp:00049284,
 author = {Winn, Aung and Tsuji, Atsushi and Sudo, Hitomi and Sugyo, Aya and Ukai, Yoshinori and Kouda, Katsushi and Kurosawa, Yoshikazu and Furukawa, Takako and Saga, Tsuneo and Higashi, Tatsuya and Ｕ Ｗｉｎｎ Ａｕｎｇ and 辻 厚至 and 須藤 仁美 and 須尭 綾 and 東 達也},
 issue = {42},
 journal = {World Journal of Gastroenterology},
 month = {Nov},
 note = {AIM
To investigate the therapeutic effect of combined
integrin α6β4-targeted radioimmunotherapy (RIT) and
PI3K/mTOR inhibitor BEZ235 in a pancreatic cancer
model.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
Key words: Radioimmunotherapy; Pancreatic cancer;
anti-integrin α6β4 antibody; Yttrium-90; NVP-BEZ235},
 pages = {7551--7562},
 title = {Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/ mTOR inhibitor},
 volume = {23},
 year = {2017}
}