2020/7/21 14:35:49
二甲双胍作为卵巢癌肿瘤干细胞靶向药物的Ⅱ期临床研究
来源:逸仙妇瘤专业版   作者:未知   浏览量:0


Phase II Clinical Trial of Metformin as a Cancer Stem Cell Targeting Agent in Ovarian Cancer 

二甲双胍作为卵巢癌肿瘤干细胞靶向药物的Ⅱ期临床研究

Brown JR, et al. JCI Insight. 2020 Jun4;5(11):133247.


Abstract 


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-reated 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). Medianoverall 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 maydrive 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.


摘要


背景

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对肿瘤干细胞样细胞

(CSCs)有影响。作为二期试验的一部分,我们评估了二甲双胍对晚期上皮性卵巢癌 (EOC)患者CSC数、癌相关间充质干细胞 (CA MSCs)和临床预后的影响。


方法

38例Ⅱc期期(n=1)/Ⅲ期(n=25)/Ⅳ期(n=12)EOC患者分别用(a)新辅助二甲双胍、减瘤手术和辅助化助化疗疗+二甲双胍或(b)新辅助化疗+二甲双胍、间歇性减瘤手术和辅助化疗+二甲双胍治疗。评估对比二甲双胍治疗的肿瘤与历史对照组的CSC数和化疗应答。主要终点是(a)乙醛脱氢酶阳性(ALDH+)CD133+ CSCs减少减少2倍或更多,(b)18个月无复发生存率超过50%。


结果

二甲双胍耐受性良好。中位无进展生存期为18.0个月个月(95%CI 14.0--21.6),,18个月无复发生存率为个月无复发生存率为59.3%(95%CI 38.6--70.5)。中位总生存期为。中位总生存期为57.9个月个月(95%CI 28.0--不可估计)。在体外,二甲双胍。在体外,二甲双胍治疗的肿瘤治疗的肿瘤ALDH+CD133+CSCs下降2.4倍,倍,且对顺铂的敏感性增加。此外,二甲双胍改变了且对顺铂的敏感性增加。此外,二甲双胍改变了CA--MSCs的甲基化标志,从而在体外阻止了的甲基化标志,从而在体外阻止了CA--MSC诱导的化疗耐药。诱导的化疗耐药。


结论

转化研究证实了二甲双胍对EOC--CSCs有影响,并提示肿瘤基质的表观遗传改变可能驱动体外铂敏感性。与此一致,二甲双胍治疗与总生存率高治疗与总生存率高于预期相关,支持在Ⅲ期研究中使用二甲双胍治疗。


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