ECE2020 Audio ePoster Presentations Pituitary and Neuroendocrinology (217 abstracts)
Metformin and everolimus: A promising combination for neuroendocrine tumors treatment
Eleonora Vitali 1 , Ilena Boemi 1 , Sara Piccini 2 , Giulia Tarantola 2 , Alessandro Zerbi 3 , Valeria Smiroldo 4 , Elisabetta Lavezzi 2 , Anna Spada 5 , Giovanna Mantovani 5 & Andrea Lania 2
1Humanitas Clinical and Research Center, Laboratory of Cellular and Molecular Endocrinology, Rozzano, Italy; 2Humanitas Clinical and Research Center, Endocrinology and Diabetology Unit, Rozzano, Italy; 3Humanitas Clinical and Research Center, Pancreas Surgery Unit, Rozzano, Italy; 4Humanitas Clinical and Research Center, Oncology Unit, Rozzano, Italy; 5IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Treatment options for neuroendocrine tumors (NET), including everolimus, are rarely curative, as NETs frequently show resistance to medical therapy. In fact, the use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signalling. Metformin seems to have anticancer effects in neuroendocrine tumors (NETs). A recent retrospective study found longer progression-free-survival in diabetic pancreatic neuroendocrine tumor (P-NET) patients treated with everolimus and/or somatostatin analogs that were also taking metformin, irrespective of glycemic status, suggesting that metformin could have direct anticancer effects on NETs. Interestingly, metformin is able to inhibit mTOR and it also blocks the IGFR-1/IRS-1/PI3K/Akt cascade, providing the rationale for the use of metformin and everolimus in combination. We investigated the effects of metformin and everolimus alone and in combination on NET cell proliferation, apoptosis and colony formation, and the involvement of the Akt and mTOR pathways, also by developing everolimus resistant QGP1-R and H727-R cells. We demonstrated that metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic-NETs cell proliferation, while no additive effects are observed on pulmonary-NETs cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation and mTOR phosphorylation in both NET cell lines. We demonstrated that in QGP1 cells, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in H727 cells. Using everolimus resistant NET cells, we confirmed that metformin maintained is anticancer effects, acting by two different pathways: Akt dependent or independent, depending on cell type, both leading to mTOR suppression. Considering the promising anticancer effects of the everolimus and metformin combination in NET cells, our results provide the rationale for its use in NET patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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