Metformin and everolimus in neuroendocrine tumours: A synergic effect?

Hue-Fontaine, Lucia; Lemelin, Annie; Forestier, Julien; Raverot, Gérald; Milot, Laurent; Robinson, Philip; Borson‐Chazot, Françoise; Lombard‐Bohas, Catherine; Walter, Thomas

doi:10.1016/j.clinre.2020.02.011

Cited by 6 publications

(10 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This phase II trial, unlike preclinical and retrospective clinical studies in patients with metastatic WD NET [ 14 , 15 , 17 , 25 , 26 ], did not confirm the anti-tumour effects of metformin in patients with grade 1 or 2 NETs. Nearly two-thirds (64%) of the patients presented disease progression before completing 6 months of treatment, no patient experience radiological response and the median PFS was only 6.3 months, similar to what has been observed with placebo in randomised phase III trials.…”

Section: Discussionmentioning

confidence: 58%

“…The combination did not inhibit proliferation in pulmonary NET cells [ 14 ]. Clinical evidence of metformin in NET is mostly from retrospective studies and also in patients treated with everolimus [ 17 , 25 , 26 ]. The largest retrospective study, the PRIME-NET, analysed 445 PNETs patients treated in 24 Italian medical centres.…”

Section: Discussionmentioning

confidence: 99%

“…Of all patients, 236 developed T2DM: 112 were treated with metformin and 124 with other hypoglycaemic drugs, including insulin. The use of metformin among patients with T2DM, in comparison with those treated with other treatments, was associated with an improvement in median PFS from 20.8 to 44.2 months, with a 51% reduction in the risk of progression or death when compared to normoglycaemic patients (HR: 0.49; 95% CI: 0.34–0.69; p < 0.00001) [ 26 ]. Another study, conducted in France, retrospectively evaluated NET patients treated with metformin and everolimus.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 213 patients received everolimus, and of these, only 48 had baseline T2DM (19 received metformin). No significant difference in median PFS was noted in the group treated with metformin and everolimus: 15.24 months versus 9.0 months for everolimus alone (HR 0.87, 95% CI: 0.54–1.39; p = 0.55) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

Glasberg¹,

Talans²,

Giollo³

et al. 2022

ecancer

View full text Add to dashboard Cite

Background Preclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET). Aim(s) To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin. Patients and methods Single-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days. Results From 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2–9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases. Conclusion Metformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

show abstract

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

Glasberg¹,

Talans²,

Giollo³

et al. 2022

ecancer

View full text Add to dashboard Cite

show abstract

“…Other studies also call the attention to metabolism-targeting agents in combinations, which highlights that these could potentially enhance the impact of sensitizing strategies and accordingly, mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism [108][109][110][111][112][113].…”

Section: Metabolic Therapymentioning

confidence: 99%

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

Sebestyén

Kopper

Dankó

et al. 2021

Pathol. Oncol. Res.

View full text Add to dashboard Cite

Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.

show abstract

PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Mpilla

Uddin

Hallak

et al. 2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro. KPT-9274 suppressed β-catenin activity via inhibition of PAK4, highlighting the cross-talk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at 150 mg/kg in combination with sub-MTD everolimus (2.5 mg/kg), significantly suppressed two PNET-derived xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.

show abstract

Metformin and everolimus in neuroendocrine tumours: A synergic effect?

Cited by 6 publications

References 16 publications

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Contact Info

Product

Resources

About