Abstract 2995: Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer

Abstract

Abstract Objective: There is growing recognition of the important role of metronomic chemotherapy for cancer treatment. Based on their unique anti-angiogenic effects, we tested the efficacy of dual albumin-bound paclitaxel (ABP), which stimulates Thrombospondin-1, and topotecan, which inhibits Hypoxia-inducible factor 1-α, chemotherapy at metronomic dosing in ovarian carcinoma. Methods: We examined the effects of ABP and topotecan in vitro (MTT) and in vivo using SKOV3ip1, HeyA8 and HeyA8-MDR orthotopic mouse models of ovarian cancer. We also examined effects on proliferation (Ki67), apoptosis (TUNEL), and angiogenesis (MVD) in tumor samples obtained at necropsy. Results: In vitro cytotoxicity assays revealed similar effects (IC50=20-60 nM) of maximum tolerated dosing (MTD) and metronomic dosing of ABP on HeyA8 tumor cells (p<0.05). In vivo therapy experiments using the SKOV3ip1 and HeyA8 tumor models demonstrated that treatment with metronomic ABP alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight, 62% and 96% respectively as compared to controls (p<0.01). Combination treatment with metronomically dosed ABP and topotecan further reduced tumor growth by 82% compared to topotecan alone (p<0.01). In the chemoresistant tumor model, HeyA8-MDR, metronomically dosed monotherapy with either cytotoxic agent had a modest effect on tumor growth however, combination therapy decreased tumor burden by 74% when compared to controls (p<0.01). Metronomic ABP monotherapy resulted in reduced cell proliferation (p<0.001), reduced tumor angiogenesis (p≤0.01), and increased apoptosis (p<0.01). Conclusions: Metronomically-dosed albumin-bound paclitaxel and topotecan offer a highly effective and novel therapeutic approach in ovarian carcinoma that merits further clinical development. Citation Format: Ashley N. Davis, Yvonne G. Lin-Liu, Rebecca A. Previs, Heather J. Dalton, Behrouz Zand, Justin Bottsford-Miller, Robert Coleman, Anil K. Sood. Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2995. doi:10.1158/1538-7445.AM2014-2995