A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer
A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer
复制标题
DOI：
10.1038/pcan.2014.20
复制
发表时间：
2014-07-01
影响因子：
4.8
通讯作者：
Pollak, M.
中科院分区：
文献类型：
--
作者：
Joshua, A. M.;Zannella, V. E.;Pollak, M.
背景：二甲双胍是呼吸链复合体1的抑制剂，广泛用于降低胰岛素抵抗。它也被描述为具有多效性，包括通过AMPK抑制mTOR激酶。临床前和流行病学研究表明前列腺癌具有调节疾病演变的能力。在这项研究中，我们的目的是(i)证明新辅助二甲双胍给药的安全性和耐受性，（ii）记录匹配活检和前列腺切除术之间增殖（Ki67）和ampk相关信号指标的变化。方法：男性在决定接受根治性前列腺切除术和手术本身之间的单臂“机会之窗”研究中接受治疗。计划40例患者，但由于累积缓慢，只有24例患者入组。21例患者可评估病理结果，22例可评估血清代谢指标。二甲双胍给药剂量为500mg t.i.d。Ki67指数采用aperio阳性像素计数算法计算，而免疫组织化学测量采用一致的H-Score。比较统计采用学生t检验和/或Wilcoxon配对对签名秩检验进行分析。结果：基线特征包括中位PSA 6 ng ml(-1) （3.22-36.11 ng ml(-1)）。药物治疗的中位持续时间为41天（18-81）。治疗耐受性良好，只有3例患者出现G3/4毒性。在每个患者和每个肿瘤的分析中，二甲双胍降低Ki67指数的相对量分别为29.5%和28.6% （P=0.0064和P= 0.0042）。P- 4ebp1染色也显著降低(P
BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomiesMETHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test.RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P =0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P