Project 7 - Metformin

项目摘要--项目7 二甲双胍的使用，一种有40年安全性和有效性记录的药物，用于治疗糖尿病 糖尿病和其他非恶性疾病与癌症存活率的提高有关 观察性研究。我们芝加哥大学(U Of C)和梅奥诊所(Mayo)的团队 独立研究表明，卵巢癌(OvCa)合并糖尿病的患者在接受二甲双胍治疗后， 预后改善。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细胞代谢改变，抑制癌细胞与间质相互作用 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 活体内卵泡刺激素。 鉴于这些发现，支持该应用的主要假设是可以使用二甲双胍 作为卵巢癌患者的癌症治疗药物。在目标1中，我们将评估二甲双胍对大鼠肾小管上皮细胞的影响。 肿瘤微环境和代谢的功能方面(糖酵解、糖原储存、脂质 动态平衡、胰岛素信号)。在目标2中，我们将使用患者来源的异种移植模型(化身)来评估 二甲双胍单独及联合化疗对肿瘤负担的影响。评估以下项目的影响 糖尿病对二甲双胍在OvCa中的作用，本实验将在正常血糖和 肥胖/高血糖小鼠。为了更好地理解二甲双胍在卵巢癌中的作用机制，我们将利用 蛋白质组学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样品对二甲双胍化疗效果的预测生物标记物 化疗+二甲双胍的随机II期试验。作为孢子的一部分，预期收集的血清 组织样本，包括新辅助化疗前后收集的配对样本 将用鸟枪式蛋白质组学方法研究二甲双胍对蛋白质表达的影响 然后是无标记量化。目标3的目标是(A)识别被改变的蛋白质和途径 用二甲双胍治疗来指导旨在了解二甲双胍作用机制的研究 患者和(B)评估在诊断时肿瘤中的蛋白质组特征是否预示着 二甲双胍治疗的有益效果。 总而言之，这些研究不仅将阐明二甲双胍治疗癌症的机制基础 新陈代谢和微环境，也提供了第一个前瞻性评估是否增加 二甲双胍化疗可提高卵巢癌患者的无进展存活率。

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.