Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer
Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer
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DOI：
10.1172/jci.insight.133247
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发表时间：
2020-06-04
期刊：
影响因子：
8
通讯作者：
Buckanovich, Ronald J.
中科院分区：
文献类型：
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作者：
Brown, Jason R.;Chan, Daniel K.;Buckanovich, Ronald J.
背景资料。流行病学研究表明，二甲双胍具有抗肿瘤作用。实验室研究表明，二甲双胍影响癌症干细胞(CSCs)。方法：38例IIC(n=1)/III(n=25)/IV(n=12)上皮性卵巢癌患者接受了(A)新辅助二甲双胍、手术和辅助化疗+二甲双胍或(B)新辅助化疗+二甲双胍、间歇性去髓鞘手术和辅助化疗+二甲双胍治疗。与历史对照组相比，二甲双胍治疗的肿瘤被评估了CSC数量和化疗反应。主要终点是(A)乙醛脱氢酶阳性(ALDH(+))CD133(+)干细胞减少2倍或更多，(B)18个月无复发存活率超过50%。结果：二甲双胍耐受性良好。中位无进展生存期18.0个月(95%可信区间14.0~21.6)，18个月无复发生存率59.3%(95%可信区间38.6~70.5)。中位总生存期为57.9个月(95%可信区间为28.0，不可估量)。二甲双胍治疗的肿瘤ALDH(+)CD133(+)CSCs减少了2.4倍，体外对顺铂的敏感性增加。此外，二甲双胍改变了CA-MSCs的甲基化信号，从而防止了CA-MSC在体外诱导的化疗耐药。结论：翻译研究证实了二甲双胍对卵巢癌干细胞的影响，并提示肿瘤间质的表观遗传学变化可能在体外驱动铂的敏感性。与此一致的是，二甲双胍治疗与好于预期的总存活率有关，支持在III期研究中使用二甲双胍。
BACKGROUND. Epidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODS. Thirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n =12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH(+)) CD133(+) CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTS. Metformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH(+)CD133(+) CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSION. Translational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.