Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient-Derived Xenografts

There is increasing pre-clinical evidence suggesting that metformin, an anti-diabetic drug, has anti-cancer properties against various malignancies including colorectal cancer (CRC). However, majority of evidence which were derived from cancer cell lines and xenografts are likely to overestimate the benefit of metformin since these models are inadequate and require supraphysiological levels of metformin. Here, we generated patient-derived xenografts (PDX) lines from 2 CRC patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for CRC. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumours 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 demonstrate 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 represent a useful platform for analysis in cancer research since it demonstrates high fidelity with parental tumour. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first pre-clinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. <br />

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