It’s a happy surprise when a drug that succeeds with one condition turns out to also work with a completely different disease. This has been the case with metformin, the most common oral medication for type II diabetes. It has unique effects, and is being studied for its use as an anti-aging and anti-cancer drug.

Not long ago, I posted a blog describing two research studies on the value of metformin to reduce prostate cancer (PCa) risk. Meanwhile, other clinical trials have been testing the therapeutic potential of metformin against advanced or metastatic PCa. Does it have the potential alone or in combination with other drugs to halt PCa spread? Numerous laboratory studies have produced analytic evidence that metformin interacts with several cancer cell processes at the molecular and genomic level. It appears to inhibit cell growth and have other anti-tumor effects. Skuli, et al. (2022) write, “Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.”^[i]

With regard to actual data from human studies, metformin use had mixed results. As far back as 10 years ago, some studies found that metformin had “anti-cancer effects in various hormone-sensitive tumors, such as breast cancer, pancreatic cancer, colon cancer, and prostate cancer.”^[ii] On the other hand, the Skuli paper reports that clinical studies of metformin use in metastatic castration-resistant PCa, use of the drug alone did not alter the disease course, nor did it improve survival or drug response when combined with docetaxel (a chemotherapy). “A recent trial combining metformin with a different anti-androgen agent, bicalutamide, in overweight and obese prostate cancer patients found that this paired treatment had no effect on PSA levels compared to bicalutamide alone.”^[iii]

Thus, questions arise, and considerably more research in the lab (in vitro) and among real life PCa patients (in vivo) is needed to answer such questions as:

1. Are metformin in vitro data able to translate from bench to bedside?
2. Does metformin affect drug resistance?
3. Can metformin be used as a generic anticancer drug for all types of tumors?
4. Which are the specific actions of metformin on the peculiarities of each type of cancer?^[iv]

Inconsistent response to metformin

An August, 2023 published paper by a Chinese research team sheds some light on inconsistent responses observed in human studies with metastatic PCa patients. Ye, et al. point to metformin’s potential use as a boost for other hormonal or chemotherapeutic treatment strategies, given that it exhibits numerous anti-cancer effects, its lack of toxic side effects, and its relatively low cost. However, they write, “… it has been reported that certain patients fail to respond to metformin. This is consistent with a previous study that preliminary demonstrated resistance to metformin treatment in various cancers due to tumor heterogeneity.”^[v]

In other words, PCa cell lines are not all created equal. There are variances in their biology, so some cell lines may develop resistance to the drug, rendering it ineffective. The team performed deep genomic analysis of the underlying mechanisms by which a) metformin affects cell signaling and metabolism, and b) some cells’ unique characteristics allow them to acquire resistance by gradually adapting to metformin’s actions. Their experiments were conducted in vitro (in the lab) with two different PCa cell lines injected in mice. The found that exposure to feed containing metformin over time, whether the drug dose was daily or every three days, gradually led to tumor resistance. If the drug was withheld then reinstated after 30 days, the tumors once again became sensitive to its effect. The knowledge thus gained about changes in the cell cycle and metabolic reprogramming brought the authors to a breakthrough hypothesis that the resistance was short-lived. As they describe it, “Interestingly, after 30 days of drug withdrawal, these MetR [metformin-resistant] cells regained metformin sensitivity, suggesting that metformin resistance may be a temporary nonmutational cell phenotype.”

Therefore, they propose that metformin, as a boost to standard-of-care treatment protocols for PCa patients with metastatic disease, be used as an intermittent treatment. At the same time, research into the genomic or molecular pathways by which PCa cells become less vulnerable to metformin should lead to developing additional treatment approaches to obstruct those pathways when administering metformin.

Hope for patients with metastatic prostate cancer

Although the Sperling Prostate Center does not offer oncologic treatments for advanced or metastatic PCa, it’s important that we post news of advances in understanding all stages of PCa. However, what we do offer is state-of-the-art imaging for the detection and diagnosis of PCa at any stage. Knowledge is power, and when patients and their doctors are equipped with thorough information, including MRI identified tumor activity anywhere in the body, it facilitates the most effective treatment plans. If you or a loved one is suspected of having PCa, contact us for more information on how we can help.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Skuli SJ, Alomari S, Gaitsch H, Bakayoko A et al. Metformin and Cancer, an Ambiguanidous Relationship.Pharmaceuticals (Basel). 2022 May 19;15(5):626
[ii] Ahn HK, Lee YH, Koo KC. Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review. Int J Mol Sci. 2020 Nov 12;21(22):8540.
[iii] Skuli, ibid.
[iv] Morale MG, Tamura RE, Rubio IGS. Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models. Biomolecules. 2022 Feb 24;12(3):357. doi: 10.3390/biom12030357.
[v] Ye J, Cai S, Feng Y, Li J et al. Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer. Signal Transduct Target Ther. 2023 Aug 16;8(1):303