Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7551
Peer-review started: June 26, 2017
First decision: July 13, 2017
Revised: July 31, 2017
Accepted: September 9, 2017
Article in press: September 9, 2017
Published online: November 14, 2017
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.
Core tip: We examined whether the therapeutic effect of 90Y-labeled anti-α6β4 integrin antibody (ITGA6B4)-mediated radioimmunotherapy (RIT) is improved by dual PI3K/mTOR inhibitor BEZ235 in the treatment of pancreatic cancer xenograft. There is no report about the combined therapeutic effects of RIT and BEZ235 in cancer treatment, though BEZ235 has been tested for its anticancer and potential radiosensitizing effect. Our studies (in vitro/in vivo) and results suggest for the first time that it is possible to improve the therapeutic efficacy by combining 90Y-ITGA6B4-RIT and BEZ235 and this combination can be a potential encouraging treatment modality in the future.