Metformin and Everolimus in Neuroendocrine Tumours: A Synergic Effect?
Open accessAbstract
OBJECTIVE: To explore potential synergy in effectiveness between metformin and everolimus, 2 inhibitors of the mTOR pathway, for neuroendocrine tumours (NET). DESIGN AND METHODS: A cohort of patients with advanced gastroenteropancreatic or lung NETs treated by everolimus were stratified in to those without diabetes, those with diabetes and without metformin, and those with diabetes with metformin. The primary endpoint was the median progression-free survival (PFS). RESULTS: A total of 213 patients were included, 165 of which were non-diabetic; among diabetic patients, 19 were treated with metformin and 29 with others anti-diabetic drugs. No significant difference in median PFS [95%CI] was found between the three groups: 10.05 months [8.27;11.83] for non-diabetic patients, 15.24 [19.88;49.43] for diabetic w/metformin, and 9.03 months [4.01;14.06] for diabetic w/o metformin group. In univariate analysis, factors significantly associated with longer PFS was a functioning NET, a number of metastatic sites<3, the absence of lung metastasis, and an uptake on Octreoscan®, but not the absence of metformin use; only uptake on Octreoscan® remained significant in multivariate analysis. CONCLUSIONS: In contrast with the literature, we did not find a synergy between everolimus and metformin in NET. Prospective studies are underway to improve the comprehension of the potential synergy regarding population and tumour type.
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mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism.
“mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism [108–113].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [112]
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New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Diagnosis and Classification of Diabetes Mellitus
American Diabetes Association (2010) · Diabetes Care · doi:10.2337/dc11-s062 · Cited by 14,019 · see citing works
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · see citing works
The 2015 World Health Organization Classification of Lung Tumors
Travis, W. D., Brambilla, E. M., Nicholson, A. G., Yatabe, Y., Austin, J. H. M., Beasley, M. B., Chirieac, L. R., Đačić, S., Duhig, E., Flieder, D. B., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000630 · Cited by 4,532 · see citing works
Everolimus for Advanced Pancreatic Neuroendocrine Tumors
Yao, J. C., Shah, M. H., Ito, T., Lombard‐Bohas, C., Wolin, E. M., Cutsem, E. V., Hobday, T. J., Okusaka, T., Capdevila, J., de Vries, E. G. E., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1009290 · Cited by 2,879 · see citing works
Self-citationThe mechanisms of action of metformin
Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287 · see citing works
Kinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515 · see citing works
Yao, J. C., Fazio, N., Singh, S., Buzzoni, R., Carnaghi, C., Wolin, E. M., Tomášek, J., Raderer, M., Lahner, H., Voi, M., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00817-x · Cited by 1,290 · see citing works
Rindi, G., Klimstra, D. S., Abedi‐Ardekani, B., Asa, S. L., Bosman, F. T., Brambilla, E. M., BUSAM, K. J., de Krijger, R. R., Dietel, M., El‐Naggar, A. K., et al. (2018) · Modern Pathology · doi:10.1038/s41379-018-0110-y · Cited by 1,164 · see citing works
Pavel, M. E., Hainsworth, J. D., Baudin, É., Peeters, M., Hörsch, D., Winkler, R. E., Klimovsky, J., Lebwohl, D., Jehl, V., Wolin, E. M., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)61742-x · Cited by 1,054 · see citing works
Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis
Coyle, C., Cafferty, F. H., Vale, C. L., & Langley, R. E. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw410 · Cited by 453 · see citing works
Arrieta, O., Barrón, F., Padilla, M.-Á. S., Avilés-Salas, A., Ramírez-Tirado, L. A., Arguelles Jiménez, M. J., Vergara, E., Zatarain-Barrón, Z. L., Hernández-Pedro, N., Cardona, A. F., et al. (2019) · JAMA Oncology · doi:10.1001/jamaoncol.2019.2553 · Cited by 179 · see citing works
Yin, M., Zhou, J., Gorak, E. J., & Quddus, F. (2013) · The Oncologist · doi:10.1634/theoncologist.2013-0111 · Cited by 157 · see citing works
Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy
Koritzinsky, M. (2015) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2015.06.003 · Cited by 101 · see citing works
Pusceddu, S., Vernieri, C., Maïo, M. D., Marconcini, R., Spada, F., Massironi, S., Ibrahim, T., Brizzi, M. P., Campana, D., Faggiano, A., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.04.010 · Cited by 88 · see citing works
A phase Ib study of everolimus combined with metformin for patients with advanced cancer
Molenaar, R. J., van de Venne, T., Weterman, M. J., Mathôt, R. A. A., Klümpen, H., Richel, D. J., & Wilmink, J. W. (2017) · Investigational New Drugs · doi:10.1007/s10637-017-0478-4 · Cited by 17 · see citing works
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Sebestyén, A., Kopper, L., Dankó, T., & Tímár, J. (2021) · Pathology and Oncology Research · doi:10.3389/pore.2021.1609802 · Cited by 110 · see citing works
PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus
Mpilla, G., Uddin, M. H., Hallak, M. N. A., Aboukameel, A., Li, Y., Kim, S. H., Beydoun, R., Dyson, G. E., Baloglu, E., Senapedis, W. T., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-1105 · Cited by 31 · see citing works
Exploring the Relationship between Obesity, Metabolic Syndrome and Neuroendocrine Neoplasms
Lan, X., Fazio, N., & Abdel-Rahman, O. M. (2022) · Metabolites · doi:10.3390/metabo12111150 · Cited by 16 · see citing works
Ruggeri, R. M., Grossrubatscher, E. M., Ciocca, E., Hasballa, I., Jaafar, S., Oldani, M., Rubino, M., Russo, F., Isidori, A. M., Colao, A. A. L., et al. (2025) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-025-09958-5 · Cited by 4 · see citing works
METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours
Glasberg, J., Talans, A., Rivelli, T. G., Recchimuzzi, D. Z., Neto, J. E. B., López, R. V. M., Hoff, P. M., & Riechelmann, R. P. (2022) · ecancermedicalscience · doi:10.3332/ecancer.2022.1369 · Cited by 4 · see citing works
Repurposing of Metformin as a Multifaceted and Multitasking Preventative and Treatment for Cancer
Chang, R. Y. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.96101 · Cited by 2 · see citing works
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Mpilla, G., Uddin, M. H., Hallak, M. N. A., Aboukameel, A., Li, Y., Kim, S. H., Beydoun, R., Dyson, G. E., Baloglu, E., Senapedis, W. T., et al. (2023) · doi:10.1158/1535-7163.c.6542856.v1
- Authors
- Hue-Fontaine, L., Lemelin, A., Forestier, J., Raverot, G., Milot, L., Robinson, P., Borson-Chazot, F., Lombard-Bohas, C., & Walter, T.
- Affiliations
- Hospices Civils de Lyon (FR)
- Lyon 1 Université (FR)
- Corresponding author
- Walter, Thomas
- Venue
- Clinics and Research in Hepatology and Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 44
- Issue
- 6
- Pages
- 954-960
- ISSN
- 2210-7401 (ISSN-L)
- OpenAlex
- W3011362651
- Cited by
- 8
- References
- 16
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2021: 3
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinics and Research in Hepatology and Gastroenterology (acceptedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- metformin, everolimus, neuroendocrine tumors, mTOR inhibitors, drug synergy, diabetes mellitus, progression-free survival, gastroenteropancreatic neuroendocrine tumors, lung neuroendocrine tumors, metastatic disease
- MeSH terms
- Everolimus, Progression-Free Survival, Aged, Antineoplastic Agents, Diabetes Mellitus, Digestive System Neoplasms, Drug Synergism, Female, Humans, Hypoglycemic Agents, Lung Neoplasms, Male, Metformin, Middle Aged, Cohort Studies, Neuroendocrine Tumors
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