Obesity-driven Metabolic and Molecular Biomarkers of Metformin Response in Endometrial Cancer

子宫内膜癌中二甲双胍反应的肥胖驱动的代谢和分子生物标志物

• 批准号: 10773270
• 负责人: Victoria Lin Bae-Jump
• 金额: $ 34.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-14 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10773270
• 关键词: Address; Aftercare; Biguanides; Biological Markers; Body mass index; Cancer Biology; Cancer Patient; Cancer cell line; Carboplatin; Cations; Cells; Cessation of life; Characteristics; Chemoresistance; Clinical Research; Clinical Trials; Data; Databases; Diabetes Mellitus; Disease; Down-Regulation; Endometrial Carcinoma; Endometrial Neoplasms; Endometrium; Energy Metabolism; Epidemiology; FRAP1 gene; Fasting; Fatty Acids; Gene Expression; Gene Expression Profile; Genotype; Glucose; Glycolipids; Goals; Growth; Growth Factor; Human; Insulin; Insulin Resistance; Knowledge; Link; Lipid Synthesis Pathway; Lipids; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Measurement; Metabolic; Metabolic Marker; Metformin; Modeling; Molecular; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oncology Group; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phase 0 Clinical Trial; Phase 0 Trial; Phase II/III Clinical Trial; Phase II/III Trial; Phenotype; Placebos; Play; Pre-Clinical Model; Production; Proliferating; Randomized; Research; Risk; Role; Serum; Signal Transduction; Testing; The Cancer Genome Atlas; Therapeutic; Thinness; Toxin; Tumor Tissue; Up-Regulation; Waist-Hip Ratio; Weight; Woman; Work; anti-cancer; cancer risk; cancer therapy; chemotherapy; clinically relevant; diabetic patient; diet-induced obesity; genetic signature; insulin regulation; insulin signaling; lipid biosynthesis; lipid metabolism; lipoprotein lipase; mTOR inhibition; metabolomics; molecular marker; mouse model; neoplastic cell; obese patients; obese person; oxidation; patient population; pre-clinical; preclinical study; predicting response; predictive marker; receptor; reproductive organ; response; standard of care; targeted agent; targeted treatment; tumor; tumor growth; tumorigenic; uptake

PROJECT SUMMARY Obesity, diabetes and insulin resistance are associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin is a biguanide that is widely used in the treatment of type 2 diabetes. Epidemiological and pre- clinical data suggest that metformin may have anti-tumorigenic activity, due to its indirect effects within the metabolic milieu (↓insulin, ↓glucose) and direct effects on tumor cells through AMPK activation/mTOR inhibition and suppression of fatty acid/lipid biosynthesis. Metformin is dependent on cation-selective transporters for entry into cells, and the multi-drug and toxin extrusion transporters, MATE1 and 2, are expressed in human EC cell lines and tumors. Thus, metformin may break the link between obesity and EC, emerging as a metabolically targeted agent for this disease. Within The Cancer Genome Atlas database, endometrioid ECs arising in obese versus non-obese women have distinguishing patterns of gene expression, including upregulation of lipoprotein lipase and modulators of the insulin/insulin growth factor-1 (IGF-1) pathway. These findings suggest that ECs arising in obesity may have distinct metabolic vulnerabilities that could be targeted for treatment. In a phase 0 clinical trial of obese EC patients, short-term metformin treatment reduced proliferation and decreased expression of the IGF-1 receptor and targets of the mTOR pathway within the endometrial tumor tissues. Responders to metformin had higher pre-treatment levels of fatty acids/glycolipids in their serum and MATE2 in their ECs, suggesting that these biomarkers might predict metformin response. Lastly, in the LKB1fl/flp53fl/fl EC mouse model, diet-induced obesity led to a doubling of tumor size, accompanied by increases in energy metabolism and lipid biosynthesis. Importantly, metformin had increased efficacy against EC in obese versus lean mice and reversed the detrimental metabolic effects of obesity in the ECs, via shunting fatty acids to beta-oxidation as opposed to lipid production. The overall goal of this proposal is to assess the contribution of indirect effects (via downregulation of insulin/IGF-1 signaling) and direct effects (via transporter-dependent cell entry, activation of AMPK/inhibition of mTOR signaling, blunting of fatty acid/lipid biosynthesis) of metformin (+/- chemotherapy) to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC [through the NRG Oncology Group]. Our central hypothesis is that predictors of metformin response (+/- chemotherapy) will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/IGF- 1 signaling, heightened fatty acid/lipid biosynthesis and higher MATE 1/2 expression. The proposed research will rigorously test this hypothesis in parallel pre-clinical and clinical studies and support it with diverse measurements of metabolic and molecular markers associated with obesity and modulated by metformin treatment. This strategy should delineate the interplay of metformin’s indirect and direct effects on tumor growth, identify metabolic and molecular biomarkers predictive of response to metformin, and define the role of this agent in obesity-driven EC treatment.

项目总结