Outcomes from late-phase efficacy studies testing metformin as a repurposed cancer therapeutic have been disappointing, leading to a re-evaluation of its potential. While initial enthusiasm has waned, new preclinical and clinical pharmacodynamic data are informing new avenues of investigation, including combination therapies and cancer prevention strategies.
Identifying Predictive Markers for Metformin Response
Researchers are now focused on identifying markers that may predict response to Complex-1 inhibitors like metformin. Mutations in the SWI-SNF complex have been proposed as potential markers. Mitochondrial mutations in genes encoding for Complex 1 have also been suggested, although their application as biomarkers may be limited by mitochondrial heteroplasmy. The transcription factor STAT3, frequently activated in malignancies, is emerging as a potential marker for drugs targeting mitochondrial metabolism, particularly in drug-resistant tumors. Biobanking of translational samples from previous trials may facilitate exploratory research to evaluate these markers and stratify patients for future trials. 'Window' studies over short time frames for selected tumors may allow stratification of patients by evaluating dynamic response and highlight additional drug combination opportunities.
Impact on Gut Microbiota and Tumor Metabolism
Animal and human studies have demonstrated that metformin can alter the metabolism of gut microbiota. Transfer of feces from obese mice treated with metformin into untreated mice inhibited tumor growth independently of changes in body mass, blood glucose, or serum insulin. This suggests that metformin treatment leads to an increase in short-chain fatty acid-producing microbes, reprogramming tumor metabolism, specifically changes in lipid homeostasis. These approaches remain largely unexplored in the clinic.
Enhancing Immunotherapy through Hypoxia Reduction
Metformin inhibits oxidative respiration, reducing hypoxia in tumor models and, more recently, in a clinical study of patients with advanced cervical cancer using fluoroazomycin arabinoside (FAZA) PET-CT. Hypoxia suppresses the anti-tumor immune response, potentially contributing to resistance to immune checkpoint immunotherapy. Preclinical data suggest that metformin could potentiate the effect of anti-PD-1 immunotherapy by remodeling the hypoxic tumor microenvironment. Furthermore, metformin may enhance tumor immunosurveillance through AMPK activation in immune cells, leading to PD-L1 phosphorylation and degradation. In syngeneic in vivo cancer models, metformin enhanced the anti-tumor effect of anti-CTLA-4 therapy. Metformin-induced AMPK activation may also downregulate CD39 and CD79 gene expression, reducing myeloid-derived suppressor cell-driven immunosuppression. Studies have shown that metformin can alter macrophage polarization from an M2 to M1-like phenotype, inhibiting tumor growth and angiogenesis, potentially driven by activation of AMPK/NF-κB signaling.
Metformin in Cancer Prevention
Metformin's role in cancer prevention is an area that has been underexplored in prospective studies. Epidemiological data provide a strong rationale for testing this hypothesis in selected groups, such as obese or insulin-resistant individuals. Early clinical trial data supports this, with one study showing metformin's potential in preventing tamoxifen-induced endometrial hyperplasia. Metformin has also been shown to suppress intestinal polyp growth in a murine model of familial adenomatous polyposis coli, and a randomized clinical trial showed that metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy following 12 months of treatment.
Prevention studies designed to identify differences in cancer incidence are challenging due to the large patient numbers and long follow-up times required. However, investigating metformin's potential as a cancer preventative for patients with cancer predisposition syndromes, such as Li-Fraumeni syndrome (LFS), allows for smaller studies and shorter follow-up. In studies of mice carrying a knock-in missense mutation of TP53, metformin increases their cancer-free survival, attributed to its direct anti-mitochondrial effect. Randomized clinical trials are now underway to evaluate whether metformin can reduce cancer incidence in this high-risk population.
In conclusion, while late-phase efficacy studies of metformin as a repurposed cancer therapeutic have been disappointing, new avenues of investigation, including combination with immunotherapy and potential as a cancer preventative agent, warrant well-designed clinical investigation. These future studies should focus on patient selection, mechanism of action, and appropriate combination strategies to maximize metformin's therapeutic potential.
