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 年安全性和有效性记录的药物，用于治疗 糖尿病和其他非恶性疾病，与癌症生存率的提高有关 我们芝加哥大学 (U of C) 和梅奥诊所 (Mayo) 的团队进行了观察性研究。 独立研究表明，接受二甲双胍治疗的卵巢癌 (OvCa) 合并糖尿病患者 我们使用 OvCa 细胞系和小鼠模型进行的临床前研究表明，预后得到改善。 二甲双胍诱导 OvCa 细胞代谢改变，抑制癌细胞与基质之间的相互作用 细胞在肿瘤微环境中，并减缓基因工程和异种移植模型的生长 体内 OvCa。 鉴于这些发现，该应用的主要假设是二甲双胍可用于 在目标 1 中，我们将评估二甲双胍对 OvCa 患者的癌症治疗作用。 肿瘤微环境和代谢的功能方面（糖酵解、糖原储存、脂质 在目标 2 中，我们将使用患者来源的异种移植模型（Avatars）来评估 单独使用二甲双胍以及与化疗联合使用对肿瘤负荷的影响。 糖尿病对二甲双胍在 OvCa 中的作用的影响，该实验将在血糖正常和 为了更好地了解二甲双胍在 OvCa 中的作用机制，我们将利用肥胖/高血糖小鼠。 蛋白质组分析以确定受二甲双胍治疗影响的关键致癌信号通路 在目标 3 中，我们将检查药效学读数并探索可能的方法。 使用我们正在进行的生物样本来预测二甲双胍对化疗效果的生物标志物 化疗±二甲双胍的随机 II 期试验作为 SPORE 的一部分，前瞻性收集血清。 和组织样本，包括新辅助化疗前后收集的配对样本± 二甲双胍，将用于使用鸟枪蛋白质组学研究二甲双胍对蛋白质表达的影响 随后进行无标记定量，目标 3 的目标是 (a) 识别发生改变的蛋白质和通路。 用二甲双胍治疗指导旨在了解二甲双胍作用机制的研究 患者和（b）评估诊断时肿瘤中的蛋白质组学特征是否预测 二甲双胍治疗的有益效果。 总的来说，这些研究不仅将阐明二甲双胍对癌症影响的机制基础 代谢和微环境，还提供了是否添加的第一个前瞻性评估 二甲双胍联合化疗可改善 OvCa 患者的无进展生存期。