A single daily tablet of metformin, a cheap diabetes drug, could delay or prevent cancer in people born with a devastating genetic fault. People with Li Fraumeni Syndrome carry a defective copy of the TP53 gene, which normally suppresses tumours, leaving them with an extraordinarily high lifetime risk of developing multiple cancers. Current care is limited to intensive surveillance and treatment after cancer appears. This trial tests whether metformin can interrupt the process that drives tumour formation in these patients. Evidence from mouse models shows that abnormal mitochondrial metabolism fuels cancer in Li Fraumeni Syndrome, and metformin reverses that metabolic defect. If the drug proves effective, it would be the first cancer prevention strategy for this condition. The trial is part of an international collaboration, and results will support a regulatory application for metformin as a preventative treatment. Success would also deepen understanding of how metabolic dysfunction drives cancer in people with TP53 mutations, with potential relevance to the many common cancers that acquire similar mutations.
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Research Question: The purpose of the MILI study is to evaluate whether metformin can prevent or delay the emergence of cancer in people with LFS. Background: Li Fraumeni Syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline or de novo pathogenic variants in TP53. Males and females with LFS have a 70% and 100% lifetime risk of cancer respectively, with around 50% having their first cancer diagnosis before the age of 46 and 31 years respectively. Typical LFS “core” malignancies include bone and soft-tissue sarcomas, breast, brain and adrenocortical cancers but less commonly lung, colon, haematological, skin, stomach and ovarian cancers. Recent evidence from LFS mouse models reveals that abnormal mitochondrial metabolism acts as a driver of cancer formation (tumorigenesis) in LFS and is reversed with the widely-used anti-diabetic drug metformin. Aims and Objectives: The primary aim is to determine the impact of metformin on the time to diagnosis of cancer in LFS, corresponding with a primary objective of comparing cancer-free survival at 5 years from randomisation between study (metformin) and control (no metformin) arms. Secondary aims are to determine the impact of metformin on: i) time to diagnosis of non-invasive/pre-cancerous lesions, ii) overall survival, iii) clinical characteristics of emerging cancers, iv) safety, tolerability and acceptability, vi) effect on quality of life and vii) lifestyle factors. Research Questions: to compare site and type of TP53 mutation with outcome, measure impact of metformin on metabolism, and investigate serum biomarkers which may correlate with tumorigenesis. Parallel studies in Canada, Germany and USA will be recruiting to a similar protocol and, upon study completion, data will be pooled in a definitive individual patient meta-analysis. This will be the world’s largest study in LFS and its first cancer prevention study. The purpose of this EME proposal is to request support for the UK MILI trial. Methods: Randomised open-label Phase II trial, n=224 adults with LFS, 1:1 randomisation to metformin (intervention) versus no metformin (control). Timelines for Delivery: 10/2022: Ethics/MHRA submission 12/2022: First Trial site opens to recruitment 01/2023: First Participant recruited 12/2024: Recruitment completed 12/2029: Study assessments completed 09/2030: Data analysis completed 12/2030: Study closed Impact/Dissemination: Trial data will support MHRA/NICE application for metformin as cancer preventative in LFS. Publications will advance understanding of tumorigenesis in LFS and somatic TP53 mutation-associated cancers.
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