Sound Biologic Foundation May Support Metformin in Li-Fraumeni Syndrome

CancerNetwork^® spoke with Payal Khincha, MBBS, MSHS, at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium about her presentation focusing on metformin as a potential therapeutic strategy for reducing the risk or delaying the onset of cancer among patients with LFS.¹

Khincha, a Lasker Clinical Research Scholar in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, highlighted how more than a decade’s worth of research has supported a “sound biologic foundation” for using metformin in patients with LFS. She described how those with LFS have elevated mitochondrial metabolism, and that disrupting this increase may help prevent cancer from developing. Based on the ability of metformin to directly inhibit this mitochondrial respiration, the agent may help mitigate the risk of cancer in those with LFS.

In her presentation, Khincha discussed how this biologic foundation has prompted an international, collaborative effort to assess how treatment with metformin may impact end points such as cancer-free survival among at-risk adults with a confirmed diagnosis of LFS. As part of this initiative, investigators are conducting the Metformin in Li Fraumeni Precision Prevention trial (MILI; ISRCTN16699730).²

Transcript:

Li-Fraumeni syndrome is a syndrome that has high cancer risks throughout [one’s] lifetime. These risks start in infancy, and [patients] also have a high risk of developing different cancer types over their lifetime, and maybe more than 1 [type]. Although we have methodologies that help detect cancers early, we currently don’t have great strategies that help either prevent the occurrence of cancer or delay the onset of cancer. My presentation is looking at the use of metformin, which is a well-known anti-diabetic drug, as an agent that could potentially either reduce the risk of cancer occurrence or delay the onset of cancer in this population. [It also looks at] thinking about ways in which we can develop clinical trials and the scientific framework to be able to answer that question.

There’s been over a decade’s worth of groundbreaking work that has laid the foundation of why we think we have a sound biologic foundation for metformin to be something that potentially works in Li-Fraumeni syndrome. Part of that goes back to looking at mitochondrial metabolism in individuals with LFS. We know that those who have LFS have increased mitochondrial metabolism—or what we call oxidative phosphorylation—compared with those who don’t. We’ve also seen, both in LFS mouse models and in humans, that disrupting that increase in mitochondrial metabolism reverses some of the processes that we think contribute to cancer development, and that metformin is an agent that directly inhibits that mitochondrial respiration. We use that as what we think is the biologic foundation for why metformin should work.

References

1. Khincha PP. Metformin as a pharmacopreventive agent in Li-Fraumeni syndrome (MILI): update on international efforts. Presented at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium; October 19-22, 2024; Philadelphia, PA.
2. Dixon-Zegeye M, Shaw R, Collins L, et al. Cancer precision-prevention trial of metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol. Trials. 2024;25(1):103. doi: 10.1186/s13063-024-07929-w.