Abstract
Abstract Background: Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite initial responsiveness to first-line standard of care, consisting of surgical debulking and chemotherapy, 8 out of 10 patients recur. In the recurrence setting, the presentation of widespread micrometastasis, which limits the usefulness of surgery, is complicated by concurrent presentation of chemoresistance. Currently, no adequate therapy is able to prevent or treat recurrence. Consequently, therapies directed against control of tumor burden can improve prognosis in EOC patients. Recently we reported the characterization of CD44+/MyD88+ EOC cells with tumor-initiating properties and inherent chemoresistance. In addition, we have identified ME-344, a novel isoflavone derivate, with potent capacity to induce cell death in these cells. Furthermore, we have developed an intra-peritoneal (i.p.) in vivo model of EOC recurrence based on the capacity of these cells to survive chemotherapy and renew the tumor. Using this model, we show the potential efficacy of ME-344 in delaying carcinomatosis and decreasing tumor burden. Methods: CD44+/MyD88+/mCherry+ EOC stem cells are injected i.p. in nude mice. Tumors are detected and consequently followed by live in vivo imaging using In Vivo FX System. Once tumors are detected, mice received 4 doses of 12 mg/kg i.p. Paclitaxel q3d or until the animals are free of disease. Mice were then randomized to maintenance with Vehicle or ME-344 (100 mg/kg i.p. q3d) and further monitored for recurrence. Recurrence is defined as appearance of tumors with ROI interior area > 2000. Tumor growth delay is defined as the difference in days when treated and control groups reach the maximal tumor burden set at ROI interior area = 10,000. Results: Mice exhibited recurrence with an average time of 6 days in the Vehicle group and 7 days in the ME-344 group. However, a significant delay in tumor kinetics was observed in the group maintained with ME-344. Maximal tumor burden, defined as ROI interior area = 10,000, was reached in the control group within 24 days and in the ME-344 group within 39 days. Thus, tumor growth was delayed for 15 days. Conclusion: Maintenance with ME-344 is able to decrease tumor burden in this very aggressive in vivo model of EOC recurrence. In this study, we show a significant delay in tumor kinetics in mice that were maintained with ME-344 following initial response to Paclitaxel. Decreasing and delaying metastatic load will allow more optimal surgical debulking and may improve survival in EOC patients. These results suggest the potential value of ME-344 therapy after 1st line standard of care in EOC patients. Citation Format: Ayesha B. Alvero, Natalia Sumi, Vinicius Craveiro, Won Duk Joo, Yang Yang-Hartwich, Gil Mor. ME-344 delays tumor kinetics in an ovarian cancer in vivo recurrence model. [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 LB-286. doi:10.1158/1538-7445.AM2013-LB-286
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