Presentation Improvement of therapeutic efficacy by combing 90Y-ITGA6B4-mediated radioimmunotherapy (RIT) with dual PI3K and mTOR inhibitor NVP-BEZ235

Winn, Aung  ,  Tsuji, Atsushi  ,  Sudo, Hitomi  ,  Ukai, Yoshinori  ,  Kouda, Katsushi  ,  Kurosawa, Yoshikazu  ,  Tsuneo Saga  ,  Higashi, Tatsuya

Aim: We recently reported the radioimmunotherapeutic effect and toxicity of Yttrium-90 labeled anti-integrin α6β4 antibody (90Y-ITGA6B4) in a pre-clinical mouse pancreatic cancer model. Despite the 90Y-ITGA6B4 showed significant anti-tumor effects, the severe myelotoxicity caused by an overdose is a major problem in radioimmunotherapy (RIT). Thus, combining RIT with other chemotherapeutic candidates is one of the options to reduce the radiation dose to bone marrow. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently mutated in human cancers and its activation alters a number of cellular processes that are stimulating proliferation, cell growth, and survival. NVP-BEZ235 (BEZ235) can potently inhibit the PI3K and mTOR kinase activity and has been used in preclinical studies in many cancers to demonstrate excellent anticancer effects. Here, we explored whether the therapeutic effect of 90Y-ITGA6B4-RIT could be improved by BEZ235 in the treatment of pancreatic cancer xenograft. Materials and 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 90Y-ITGA6B and BEZ235 by using western blotting method. The cytotoxic effect of BEZ235 was investigated with colony formation assay. Enhancement of therapeutic efficacy by BEZ235 oral administration was evaluated by 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 effects of combined treatment 90Y-ITGA6B4 plus BEZ235, or each arm alone. Results: We found that that phosphorylation of p-Akt (p-Akt), 4EBP1 (p-4EBP1) and S6 (p-S6) was inhibited by BEZ235. Cell colony forming was additively suppressed by the combination of RIT and BEZ235. Mice received treatments showed reduction in tumor volumes (P < 0.05), decreased Ki-67-positive cells and 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.
30th Annual Congress of the European Association of Nuclear Medicine

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