Author: Sudo, Hitomi ; Ukai, Yoshinori ; Kouda, Katsushi ; Saga, Tsuneo ; Higashi, Tatsuya ; Aung, Winn ; Sugyo, Aya ; Tsuji, Atsushi B ; Kurosawa, Yoshikazu ; Furukawa, Takako

AIMTo investigate the therapeutic effect of combined integrin α₆β₄-targeted radioimmunotherapy (RIT) and PI3K/mTOR inhibitor BEZ235 in a pancreatic cancer model.METHODSPhosphorylation 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.RESULTSWe 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.CONCLUSIONThe 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.

21 Jun 2016·Oncotarget

Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-α6β4 integrin antibody

Article

Author: Sugyo, Aya ; Furukawa, Takako ; Aung, Winn ; Ukai, Yoshinori ; Kouda, Katsushi ; Tsuji, Atsushi B. ; Sudo, Hitomi ; Saga, Tsuneo ; Kurosawa, Yoshikazu

The contribution of integrin α6β4 (α6β4) overexpression to the pancreatic cancer invasion and metastasis has been previously shown. We have reported immunotargeting of α6β4 for radionuclide-based and near-infrared fluorescence imaging in a pancreatic cancer model. In this study, we prepared yttrium-90 labeled anti-α6β4 antibody (90Y-ITGA6B4) and evaluated its radioimmunotherapeutic efficacy against pancreatic cancer xenografts in nude mice. Mice bearing xenograft tumors were randomly divided into 5 groups: (1) single administration of 90Y-ITGA6B4 (3.7MBq), (2) double administrations of 90Y-ITGA6B4 with once-weekly schedule (3.7MBq x 2), (3) single administration of unlabeled ITGA6B4, (4) double administrations of unlabeled ITGA6B4 with once-weekly schedule and (5) the untreated control. Biweekly tumor volume measurements and immunohistochemical analyses of tumors at 2 days post-administration were performed to monitor the response to treatments. To assess the toxicity, body weight was measured biweekly. Additionally, at 27 days post-administration, blood samples were collected through cardiac puncture, and hematological parameters, hepatic and renal functions were analyzed. Both 90Y-ITGA6B4 treatment groups showed reduction in tumor volumes (P < 0.04), decreased cell proliferation marker Ki-67-positive cells and increased DNA damage marker p-H2AX-positive cells, compared with the other groups. Mice treated with double administrations of 90Y-ITGA6B4, exhibited myelosuppression. There were no significant differences in hepatic and renal functions between the 2 treatment groups and the other groups. Our results suggest that 90Y-ITGA6B4 is a promising radioimmunotherapeutic agent against α6β4 overexpressing tumors. In the future studies, dose adjustment for fractionated RIT should be considered carefully in order to get the optimal effect while avoiding myelotoxicity.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	JP	Perseus Proteomics, Inc.	-
Neoplasms	Preclinical	JP	National Institute of Radiological Sciences	-

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