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The world of drug discovery is a frustrating, delicate world. Scientists spend years working on fine-tuning molecules to improve their function, make them safer, or even just make them easier to give to patients. We have a catalog of drugs that work on single, specific proteins only found in cancer cells, or immune cells, you name it.
And then there’s metformin.
Metformin was originally developed from a French lilac used in folk medicine to treat diabetes, but has since become a widely studied drug for the treatment of polycystic ovarian syndrome, cancer, and cardiovascular diseases as well. While the ways in which metformin works are not fully understood, it seems that it may target several pathways or functions, leading to varied applications. Metformin is attractive to researchers and clinicians for these uses for many reasons, not the least of which is that it is a very well tolerated drug and fairly inexpensive. Unfortunately, even with all the work being done to make metformin into a cancer drug, the research shows that its effect on tumors is weak. Some are trying to get around this issue by using metformin in fancy drug delivery systems, including making metformin into a chain, called a polymer, and using that polymer to contain and deliver other cancer therapies at the same time, like weaving a basket to carry your lunch. However, recent research out of Vienna implies that we can improve the ability of metformin to fight tumors through a much simpler method: intermittent fasting.
The idea is this: metformin is used as a diabetic drug because it is able to reduce high blood glucose levels (although it has little effect on normal blood glucose levels, making it safe for non-diabetic patients). We know from years of study that cancer cells change their metabolism, or ways in which they produce energy, to be more glucose dependent, but that they are also able to switch to other metabolic pathways when under stress. Intermittent fasting, defined in this study as going 24 hours at a time without food, alternating with days when you can eat at-will, leads to a significant drop in blood glucose levels during fasting days, known as hypoglycemia. This starves tumors of glucose they need to thrive and pushes them towards other methods of energy production. However, when metformin is given during these periods of hypoglycemia, it is able to inhibit these metabolic pathways in cancer cells. Strikingly, neither fasting alone nor metformin alone was able to inhibit tumor growth in any meaningful way, but when metformin was given in the middle of a fasting period, it was able to fully shut down cell metabolism and completely halt tumor growth in mouse models of colorectal cancer and melanoma.
While this data is exciting, there are some drawbacks to the implementation of this research. First, most of this work was done either in cell lines in culture or in tumor models that are not known to be fully representative of human tumors. While they did use some patient-derived tumors, more meaningful studies should be done on tumors implanted into their organs of origin to best ensure that these trends can be reproduced; only one of the tumor models used in this study was implanted in the organ of origin. Fasting may also be difficult for some cancer patients, particularly if they are also undergoing chemotherapy, but in some cases, the ability to use a well-tolerated drug like metformin in combination with fasting may lead to a much less painful treatment regimen than many that are currently available.
The most impactful thing about this research is that it indicates that lifestyle changes and cancer therapy can go hand in hand, and that we as cancer researchers should be willing to look outside of the box when working on improvements to cancer therapies. This particular treatment may not end up making its way to the clinic, but it does show that there are many ways to target cancer, and that we need to work harder on finding the right path for patients, which may include lifestyle changes.
All images © Wikipedia Commons
Image 1: Metformin: A simple but powerful molecule!
Image 2: French lilac, from which metformin was originally derived.
Elgendy, M., et al. (2019). Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis. Cancer cell, 35(5), 798-815. https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30152-7#%20
Momcilovic, M., & Shackelford, D. B. (2019). Teaching an Old Drug New Tricks. Cancer cell, 35(5), 709-711. https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30203-X