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Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.

ABSTRACT: We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

SUBMITTER: Schuler KM

PROVIDER: S-EPMC4329001 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.

Schuler Kevin M KM Rambally Brooke S BS DiFurio Megan J MJ Sampey Brante P BP Gehrig Paola A PA Makowski Liza L Bae-Jump Victoria L VL

Cancer medicine 20141121 2

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamyc ...[more]

PMID: 25417601

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Project description:BACKGROUND:Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. METHODS:METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London. DISCUSSION:This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. TRIAL REGISTRATION:EudraCT number 2014-005193-11 . Registered on September 09, 2015.

Project description:BackgroundSitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.MethodsPatients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib-nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.ResultsTen patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib-nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.ConclusionsThe SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib-nivolumab and revealed patients with distinct tumor biology behavior.Trial registration numberNCT03575598.

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Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.

Publications

Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.

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