Project 7 - Metformin

项目7——二甲双胍

• 批准号: 8932130
• 负责人: Ernst Lengyel
• 金额: $ 33.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932130
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Biological Assay; Biological Markers; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cells; Chicago; Clinic; Clinical; Clinical Trials; Cohort Studies; Data; Diabetes Mellitus; Diabetic mouse; Diagnosis; Enrollment; Fibroblasts; Future; Genetic Engineering; Glycogen; Glycolysis; Goals; Growth; Homeostasis; Hyperglycemic Mice; In Vitro; Inflammatory; Label; Lipids; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Medicine; Metabolic; Metabolic Pathway; Metabolism; Metformin; Mus; Neoplasm Metastasis; Non-Malignant; Obesity; Observational Study; Oncogenic; Oral; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase II Clinical Trials; Placebos; Progression-Free Survivals; Proteins; Proteome; Proteomics; Randomized; Reporting; Research; Research Design; Safety; Sampling; Serum; Shotguns; Signal Pathway; Stromal Cells; Syndrome; Testing; Therapeutic; Time; Tissue Sample; Treatment Efficacy; Tumor Burden; Universities; Work; Xenograft Model; Xenograft procedure; antitumor effect; base; cancer cell; cell type; chemotherapy; cost; diabetic; fatty acid oxidation; glycogen metabolism; improved; in vivo; insight; insulin signaling; metabolic abnormality assessment; mortality; mouse model; neoplastic cell; non-diabetic; outcome forecast; phase II trial; pre-clinical; preclinical study; prospective; protein expression; research study; response; translational study; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumorigenic

PROJECT SUMMARY – Project 7 Use of metformin, a medicine with a 40-year track record of safety and efficacy for the treatment of diabetes and other non-malignant conditions, has been associated with improved cancer survival in observational studies. Our groups at the University of Chicago (U of C) and the Mayo Clinic (Mayo) have independently shown that ovarian cancer (OvCa) patients with diabetes who are treated with metformin have an improved prognosis. Our preclinical studies, using OvCa cell lines and mouse models, showed that metformin induces metabolic alterations in OvCa cells, inhibits interactions between cancer cells and stromal cells in the tumor microenvironment, and slows growth of both genetically engineered and xenograft models of OvCa in vivo. In view of these findings, the primary hypothesis underlying this application is that metformin can be used as a cancer therapeutic in patients with OvCa. In Aim 1, we will evaluate the effect of metformin on cells in the tumor microenvironment and on functional aspects of metabolism (glycolysis, glycogen storage, lipid homeostasis, insulin signaling). In Aim 2, we will use patient-derived xenograft models (Avatars) to evaluate the effect of metformin alone and in combination with chemotherapy on tumor burden. To assess the impact of diabetes on the action of metformin in OvCa, this experiment will be performed in both normoglycemic and obese/hyperglycemic mice. To better understand the metformin mechanism of action in OvCa, we will utilize proteomic profiling to identify the key oncogenic signaling pathways affected by metformin treatment in the patient-derived xenografts. In Aim 3, we will examine pharmacodynamic readouts and explore possible predictive biomarkers of metformin's effect with chemotherapy using biospecimens from our ongoing randomized phase II trial of chemotherapy ± metformin. As part of the SPORE, prospectively collected serum and tissue samples, including paired samples collected before and after neo-adjuvant chemotherapy ± metformin, will be used to study the effect of metformin on protein expression using shotgun proteomics followed by label-free quantification. The goal of Aim 3 is to (a) identify proteins and pathways that are altered with metformin treatment to guide research aimed at understanding the mechanism of metformin action in patients and (b) assess whether a proteomic signature in the tumor at the time of diagnosis predicts a beneficial effect of metformin treatment. Collectively, these studies will not only elucidate the mechanistic basis for metformin's effects on cancer metabolism and the microenvironment, but also provide the first prospective assessment of whether adding metformin to chemotherapy improves progression-free survival in OvCa patients.

项目摘要 - 项目7 使用二甲双胍，一种具有40年安全性和效率记录的药物 糖尿病和其他非恶性状况与改善的癌症生存有关 观察性研究。我们在芝加哥大学（C）和梅奥诊所（Mayo）的小组 独立地表明，接受二甲双胍治疗的糖尿病患者（OVCA）患者 改善的预后。我们使用OVCA细胞系和小鼠模型的临床前研究表明 二甲双胍诱导OVCA细胞的代谢改变，抑制癌细胞与基质之间的相互作用 肿瘤微环境中的细胞，并减慢一般工程和异种移植模型的生长 OVCA在体内。 鉴于这些发现，此应用的主要假设是可以使用二甲双胍 作为OVCA患者的癌症治疗。在AIM 1中，我们将评估二甲双胍对细胞中细胞的影响 肿瘤微环境和代谢的功能方面（糖酵解，糖原储存，脂质 稳态，胰岛素信号传导）。在AIM 2中，我们将使用患者衍生的Xenographic模型（化身）来评估 单独二甲双胍和与化学疗法结合对肿瘤负担的影响。评估 糖尿病对二甲双胍在OVCA的作用，该实验将在正常血糖和 肥胖/高血糖小鼠。为了更好地了解OVCA的二甲双胍作用机制，我们将利用 蛋白质组学分析以识别受二甲双胍治疗影响的关键致癌信号通路 患者衍生的Xenographictic。在AIM 3中，我们将检查药效学读数并探索可能 二甲双胍对化学疗法作用的预测生物标志物，使用我们正在进行的生物测量 化学疗法±二甲双胍的随机II期试验。作为孢子的一部分，前瞻性收集的系列 和组织样品，包括在新辅助化学疗法±之前和之后收集的成对样品± 二甲双胍将用于研究二甲双胍对使用shot弹枪蛋白质组学的蛋白质表达的影响 然后进行无标签定量。目标3的目的是（a）识别改变的蛋白质和途径 通过二甲双胍治疗来指导研究旨在了解二甲双胍作用的机制 患者和（b）评估诊断时肿瘤中的蛋白质组学特征是否预测A 二甲双胍治疗的有益作用。 总的来说，这些研究不仅将阐明二甲双胍对癌症影响的机械基础 新陈代谢和微环境，但也提供了首先评估是否添加 化学疗法的二甲双胍可改善OVCA患者的无进展生存率。