There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% ( P < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% ( P = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. Mol Cancer Ther; 16(9); 2035–44. ©2017 AACR .

中文翻译：

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二甲双胍抑制大肠癌患者异种移植物中的细胞增殖和生物能。

越来越多的临床前证据表明，二甲双胍是一种抗糖尿病药，对包括结肠直肠癌在内的各种恶性肿瘤具有抗癌作用。但是，多数证据来自癌细胞系和异种移植物，可能会高估二甲双胍的益处，因为这些模型不足，需要超生理水平的二甲双胍。在这里，我们从2位大肠癌患者中产生了患者源性异种移植（PDX）品系，以评估二甲双胍和5-氟尿嘧啶（5-FU）（大肠癌的一线药物治疗）的特性。口服二甲双胍（150 mg / kg）作为单一药物，当口服24天时，可抑制两种PDX肿瘤的生长至少50％（P <0.05）。在其中一种PDX模型中，与5-FU（25 mg / kg）并用的二甲双胍可导致85％（P = 0.054）的生长抑制。从PDX生成的类器官的离体培养表明，二甲双胍可通过执行代谢变化来减少氧气消耗并激活AMPK介导的途径来抑制生长。此外，我们还使用下一代测序（NGS）对来自患者的系列PDX样品和相应的亲本组织进行了遗传表征。我们的NGS试点研究表明PDX代表了癌症研究中一个有用的分析平台，因为它证明了亲本肿瘤的高保真度。此外，对PDX的NGS分析可能对确定药物反应的遗传学识别有用。这是首次使用PDX和PDX衍生的类器官来研究二甲双胍在结直肠癌中的疗效的临床前研究。分子癌疗法；16（9）; 2035–44。©2017 AACR。