Division of Cancer Studies, Cancer Epidemiology Group, Research Oncology, King's College London, 3rd Floor, Bermondsey Wing, Guy's Hospital, London, SE1 9RT, UK.
Guy's and St Thomas' NHS Foundation Trust, London, UK.
BMC Cancer. 2017 Jul 21;17(1):494. doi: 10.1186/s12885-017-3458-3.
Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa.
METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London.
This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place.
EudraCT number 2014-005193-11 . Registered on September 09, 2015.
二甲双胍是一种常用于治疗 2 型糖尿病的双胍类口服降糖药。除了降血糖作用外，二甲双胍还与多种实体瘤（包括前列腺癌）的癌症发病率降低有关。然而，这些观察结果的潜在生物学机制在前列腺癌中尚未完全阐明。一种假设是，间接降低胰岛素水平可能具有抗肿瘤作用，因为升高的胰岛素和胰岛素样生长因子-1（IGF-1）水平在前列腺癌的发展和进展中发挥作用。此外，二甲双胍是激活蛋白激酶（AMPK）的有效激活剂，而 AMPK 又会抑制哺乳动物雷帕霉素靶蛋白（mTOR）和其他信号转导机制。这些直接作用可导致细胞增殖减少。鉴于其广泛的可用性和可耐受的副作用谱，二甲双胍代表了一种有吸引力的潜在治疗选择，适用于患有前列腺癌的男性。因此，需要进行临床试验以研究其在前列腺癌中的生物学机制。
METAL 是一项随机、安慰剂对照、双盲、机会窗研究，旨在研究二甲双胍在前列腺癌中的生物学机制。100 名新诊断为局限性前列腺癌且计划接受根治性前列腺切除术的患者将按 1:1 随机分为接受二甲双胍（1g 每日两次）或安慰剂治疗四周（+/-1 周），然后再进行前列腺切除术。将从诊断性活检和前列腺切除术标本中采集组织。主要终点是安慰剂组和二甲双胍组治疗前后脂肪酸合酶（FASN）/AMPK 通路标志物表达水平的差异。次要终点包括安慰剂组和二甲双胍组治疗前后增殖指标（ki67 和 TUNEL）表达水平的差异。METAL 目前在盖伊和圣托马斯医院和伦敦皇家马斯登医院开放招募。
这项针对因接受根治性前列腺切除术而患有局限性前列腺癌的男性的二甲双胍与安慰剂的随机安慰剂对照双盲试验旨在阐明二甲双胍在前列腺癌细胞中的作用机制，然后应能进行更大规模的分层试验。
EudraCT 编号 2014-005193-11。于 2015 年 9 月 9 日注册。
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