Abstract 5090: A novel IKKβ inhibitor, IMD-0354, inhibits ovarian cancer dissemination by inhibiting VEGF production from cancer cells - the potential for a novel anti-angiogenic therapy.

Abstract

Abstract Purpose: The prolongation of disease-free survival in patients with advanced ovarian cancer by the anti-VEGF (vascular endothelial growth factor) monoclonal antibody (bevacizumab) has been shown in several large clinical trials, demonstrating that an anti-angiogenic therapy is one of promising treatment options. However, the effect of bevacizumab on the overall survival of patients is very limited and it is too expensive to use for every patient in the world. Therefore, the development of a novel anti-angiogenic drug composed of low-molecular-weight compounds would be a powerful armament for the treatment of ovarian cancer. Since it is known that NF-κB signaling promotes VEGF expression, we determined to identify the potential of a novel IKKβ inhibitor, IMD-0354, as an anti-angiogenic drug for ovarian cancer treatment in vitro and in vivo. Methods: A novel IKKβ inhibitor, IMD0354, was a generous gift from IMMD inc. (Tokyo, Japan). The activation of IKKβ in various ovarian cancer cell lines was examined by Western Blotting. The effect of IMD-0354 on ovarian cancer cell lines was analyzed via cell cycle analysis, in vitro cell proliferation or invasion assay. The inhibitory effect of IMD-0354 against VEGF production from cancer cells was examined by luciferase activity assay and in vitro tube formation assay. Using a xenograft model, the inhibitory effect of IMD-0354 against peritoneal dissemination of ovarian cancer cells was analyzed. Results: The higher dose treatment of IMD-0354 (≥ 1 μM) caused the G1 arrest of ovarian cancer cells and subsequently inhibited the cell growths. In contrast, the lower doses of IMD-0354 (≤ 100 nM) treatment decreased the expression of VEGF mRNA transcript levels as well as VEGF promoter activities in a concentration-dependent manner without impairing cell viabilities. In SKOV-3ip1 ovarian cancer xenografts, i.p. treatment with IMD-0354 (30 mg/kg daily) significantly reduced tumor burden and the number of peritoneal implants. Immunohistochemical analysis of inoculated tumors with anti-CD-31 antibody revealed a marked inhibition of blood vessel formation by the treatment of IMD-0354. Conclusion: In most ovarian cancer cells, IKKβ is constitutively phosphorylated, suggesting NF-κB signaling could be a potential molecular target. A novel IKKβ inhibitor, IMD-0354, strongly suppressed VEGF production from ovarian cancer cells and finally inhibited the cell growth. Accordingly, in an ovarian cancer xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of with blood vessel formation. IMD-0354 is a stable low molecular weight drug and has already administered safely to humans in other clinical trials. Anti-angiogenic therapy using this drug has the potential to be an alternative option to cure of ovarian cancer patients in the future. Citation Format: Yasuto Kinose, Kenjiro Sawada, Kae Hashimoto, Seiji Mabuchi, Ken-ichirou Morishige, Tadashi Kimura. A novel IKKβ inhibitor, IMD-0354, inhibits ovarian cancer dissemination by inhibiting VEGF production from cancer cells - the potential for a novel anti-angiogenic therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2013-5090