Abstract 5176: E7386, an orally active CBP/beta-catenin modulator, effects tumor microenvironment, resulting to the enhancement of antitumor activity of lenvatinib

E7386, a novel orally active CBP/beta-catenin modulator, has an impact on cancer cells with aberrant activation of Wnt/beta-catenin signaling pathway driven by adenomatous polyposis coli (APC) mutation or beta-catenin mutation and shows significant antitumor activity in xenograft models. CBP/beta-catenin transcriptional activation has an important role in not only malignancy of cancer cells but also regulation of tumor microenvironment such as fibroblast, pericyte, endothelial cells and immune cells. In this study, we investigated E7386 effect on tumor microenvironment and if it leads to enhance antitumor activity of lenvatinib. Lenvatinib is a potent anti-angiogenic inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and other proangiogenic and oncogenic kinases. Firstly, we tested the combination of E7386 with lenvatinib in Wnt-1 tumor isogenic models, where tumors isolated from MMTV-Wnt1 transgenic mice were inoculated in mice. While E7386 and lenvatinib individually suppressed tumor growth and caused tumor dormancy, the combination resulted in approximately 75% tumor reduction. To clarify the effect on tumor microenvironment, we tested an isograft model of 4T1 murine breast cancer cells which was resistant to E7386 in vitro proliferation. E7386 and lenvatinib individual treatments showed a significant antitumor effect, but the antitumor effect of the combination was significantly superior to that of each mono-treatment. Therefore, we compared effects of E7386 and lenvatinib on tumor microenvironment in immunohistochemical analysis using CD31 Ab as an endothelial marker and alpha-SMA Ab as a pericyte and cancerous fibroblast marker. E7386 significantly decreased alpha-SMA positive cells and microvessel density in tumors. In addition, remaining tumor vessels were not covered with pericytes. In lenvatinib treated tumors, greater reduction of microvessel density was observed than in E7386 treated tumors, but tumor vessels covered with pericytes, which are known to be resistant against VEGF inhibitors, were remained. In combination treatment, most of the tumor vessels disappeared. The enhancement of antitumor activity in the combination was also observed in SEKI human melanoma xenograft model which is relatively resistant to lenvatinib. These data suggest E7386 sensitizes tumor to lenvatinib through the modulation of the tumor microenvironment that is resistant to VEGF inhibitors. Taken together, E7386 shows