Project 7 - Metformin

项目7——二甲双胍

• 批准号: 9149471
• 负责人: Ernst Lengyel
• 金额: $ 33.83万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9149471
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Biological Assay; 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; cancer survival; 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; pharmacodynamic biomarker; phase II trial; pre-clinical; preclinical study; predicting response; predictive marker; prospective; protein expression; proteomic signature; research study; response biomarker; three dimensional cell culture; 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.

项目概要-项目7 使用二甲双胍，一种具有40年安全性和有效性跟踪记录的药物， 糖尿病和其他非恶性疾病，已与改善癌症存活率， 观察性研究我们在芝加哥大学（U of C）和马约诊所（马约）的团队已经 独立研究表明，接受二甲双胍治疗的卵巢癌（OvCa）糖尿病患者 改善预后。我们使用OvCa细胞系和小鼠模型进行的临床前研究表明， 二甲双胍诱导OvCa细胞的代谢改变，抑制癌细胞和基质细胞之间的相互作用 肿瘤微环境中的细胞，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，本申请的主要假设是二甲双胍可用于 作为卵巢癌患者的癌症治疗药物。在目的1中，我们将评估二甲双胍对细胞的影响， 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）。在目标2中，我们将使用患者来源的异种移植模型（Avatars）来评估 二甲双胍单药治疗和与化疗联合治疗对肿瘤负荷的影响。受影响的评估 糖尿病对二甲双胍在OvCa中作用的影响，该实验将在血糖正常和 肥胖/高血糖小鼠。为了更好地了解二甲双胍在OvCa中的作用机制，我们将利用 蛋白质组分析，以确定二甲双胍治疗影响的关键致癌信号通路。 患者来源的异种移植物。在目标3中，我们将检查药效学读数，并探索可能的 使用我们正在进行的生物标本， 化疗±二甲双胍的随机II期试验。作为SPORE的一部分，前瞻性采集血清 和组织样本，包括新辅助化疗前后采集的配对样本± 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）识别被改变的蛋白质和途径 指导旨在了解二甲双胍作用机制的研究， （B）评估在诊断时肿瘤中的蛋白质组特征是否预测了肿瘤中的蛋白质组特征， 二甲双胍治疗的有益效果。 总的来说，这些研究将不仅阐明二甲双胍对癌症作用的机制基础， 代谢和微环境，而且还提供了第一个前瞻性评估， 二甲双胍联合化疗可改善OvCa患者的无进展生存期。