Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties.
Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties.
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DOI：
10.1158/0008-5472.can-17-3993
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发表时间：
2018-08-01
期刊：
影响因子：
11.2
通讯作者：
Godwin AK
中科院分区：
文献类型：
--
作者：
Hirst J;Pathak HB;Hyter S;Pessetto ZY;Ly T;Graw S;Koestler DC;Krieg AJ;Roby KF;Godwin AK
用于上皮性卵巢癌（EOC）一线治疗的药物开发已经停滞了近三十年。用于初级药物筛选的传统细胞培养方法并不总是准确地反映临床疾病。为了克服这一障碍，我们在三维（3D）细胞培养物中培养了一组EOC细胞系，以形成多细胞肿瘤球体（MCTS）。我们对这些MCTS进行了EOC的分子和细胞特征的表征，并与使用二维（2D）细胞培养生长的细胞进行了比较筛选，以鉴定以前未被重视的抗癌药物。MCTS表现出更大的耐药性化疗药物，衰老和缺氧的迹象，并表达了一些干细胞相关的转录，包括ALDH 1A和CD 133。使用临床上重新利用的药物库，我们确定了在MCTS中具有优先活性的候选物超过2D培养细胞。先导化合物之一，双考克斯/LOX抑制剂licofelone，逆转了卵巢MCTS的干细胞样特性。在卵巢MCTS模型和患者来源的肿瘤异种移植物（PDX）模型中，Licofelone也与紫杉醇协同作用。重要的是，与紫杉醇（115天）、利卡非隆（37天）或载体（30天）相比，利卡非隆与紫杉醇的组合延长了小鼠的中位生存期（>141天）。通过与溶剂（HR=0.037）和紫杉醇（HR=0.017）相比的Mantel-Haenszel风险比证实了疗效增加。这些结果首次确定了一种不受重视的抗炎药物，可以逆转卵巢癌的化疗耐药性，突出了临床评估利可非龙联合一线化疗治疗原发性和化疗难治性EOC的必要性。
Drug development for front-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anti-cancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133. Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft (PDX) model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel hazard ratio compared to vehicle (HR=0.037) and paclitaxel (HR=0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with front-line chemotherapy in primary and chemotherapy-refractory EOC.