In recent years, abundant preclinical studies have demonstrated that metformin holds promise as an antitumor agent capable of halting the progression of breast, colon, lung and prostate cancers. Nevertheless, it should be noted that the animal models adopted in these studies fail to recapitulate the pathological features of human malignancies accurately, and supra-physiological metformin concentrations were required to elicit antitumor activity.
In this research, a team led by Dr. Min-Han Tan from the Institute of Bioengineering and Nanotechnology at A*STAR evaluated the antitumor efficacy of metformin in colorectal cancer models that better recapitulate the clinical manifestations of human cancer, achieving significant research breakthroughs.
Patient-derived Xenograft Mouse Models
Specifically, the research team harvested malignant tissue specimens from two colorectal cancer patients and implanted these tissues into immunocompromised mice. Next-generation sequencing (NGS) analysis verified that patient-derived tumor xenografts retained the genetic, molecular and histological signatures of the original primary tumors.
Subsequently, the researchers utilized these xenograft models to characterize tumor responsiveness to metformin monotherapy as well as 5-fluorouracil (5-FU), the first-line standard regimen for clinical colorectal cancer treatment.
Antitumor Activity Achieved at Physiologically Relevant Concentrations
Experimental outcomes revealed that metformin monotherapy suppressed tumor growth by a minimum of 50% over a 24-day treatment period. When combined with 5-fluorouracil, the drug combination yielded an 85% growth inhibition rate against the tumor grafts derived from one of the enrolled patients.
Notably, the metformin concentration applied in this experiment was equivalent to the therapeutic plasma concentration administered clinically for diabetes management in humans. Dr. Tan emphasized the great significance of this finding.
He elaborated: "Conventional research approaches typically inject cultured cancer cell lines into recipient animals instead of implanting intact patient tumor tissues into mice. Establishing stable cell lines for such models demands elevated levels of glucose, insulin and growth factors within the artificial culture microenvironment. We hypothesize that this artificial niche accounts for the high metformin dosages demanded by previous studies for tumor suppression. By contrast, our work validated metformin's antitumor effects at the clinically relevant doses routinely prescribed for diabetic patients."
The First Research Using Patient-derived Tumor Xenografts for Metformin Assessment
Further investigation was conducted to clarify the molecular mechanism underlying metformin's anticancer property. Experimental data indicated that this widely used drug exerts therapeutic effects via two pathways: activating intracellular signaling cascades associated with tumor suppression and reducing oxygen consumption in malignant cells.
To date, this study represents the first investigation exploring metformin against colorectal cancer on the basis of patient-derived tumor xenograft models. Dr. Tan concluded: "Our work corroborates the therapeutic potential of metformin against colorectal cancer and elucidates its underlying molecular mechanisms. Despite the improved fidelity of our animal models, further clinical trials are still warranted to translate these preclinical findings into clinical applications for human patients."
