Mechanisms of Biguanide Sensitivity in GBM

GBM 中双胍敏感性的机制

基本信息

批准号：
10439389
负责人：
Biplab Dasgupta
金额：
$ 50.42万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439389
关键词：
Algorithms Antineoplastic Agents Biguanides Blood - brain barrier anatomy Brain Cell Death Cell Line Cell membrane Classification Clinical Trials Combined Modality Therapy Complex Data Data Analyses Diffusion Dose FDA approved Gene Expression Generations Genes Glioblastoma Glucose Glycolysis Goals Growth In Vitro Investigation Kidney Knowledge Liver Malignant Neoplasms Malignant neoplasm of lung Messenger RNA Metabolic Metformin Methods Methylation Mitochondria Molecular Molecular Analysis Mutation Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Oxidative Phosphorylation POU2F1 gene POU2F2 gene Pathway interactions Pharmaceutical Preparations Proteomics Pump Pyruvate Regulation Resistance Safety Signal Transduction Specificity Stable Isotope Labeling Testing The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissues Toxic effect Translating Tumor Subtype Validation adenylate kinase base blood-brain barrier crossing cell growth classification trees clinical development cohort complement C2a efficacy evaluation efficacy study efficacy testing experimental analysis improved in vitro testing in vivo inhibitor inhibitor therapy kinase inhibitor metabolic phenotype molecular marker mouse model neoplastic cell novel novel therapeutics pharmacokinetics and pharmacodynamics promoter protein expression pyruvate dehydrogenase regression trees resistance mechanism responders and non-responders response safety study sensor stem stem cells success temozolomide therapy resistant tumor tumor growth tumor microenvironment

项目摘要

Project Summary/Abstract The biguanide drug metformin that is widely used for the management of Type 2 diabetes is being evaluated as an anti- neoplastic agent in cancer trials including GBM (NCT02780024, NCT03243851). The various mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth, cell death, gene expression, and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) are currently under investigation. Diffusion of metformin across the plasma membrane occurs slowly. Its entry is facilitated by two transporters OCT1 and OCT2 that are not well expressed outside the liver and kidney. This presents a problem due its lack of accumulation in other tissues at therapeutic concentrations. Therefore, identification of tumor subtypes that respond better to lower concentrations of metformin may be leveraged for targeted metformin therapy. Metformin GBM trials may be unsatisfactory since there are no molecular markers to distinguish metformin responders from non-responders. Identification of molecular markers may greatly improve metformin and other MCI-i-based therapy in GBM. We identified that a pyruvate dehydrogenase subunit (PDHA1) is a possible molecular beacon for MCI-i therapy in GBM. We will test this in vitro and in vivo. We also found that the cellular energy sensor AMPK provides resistance to MCI-i therapy in a subset of GBM. We will test if a brain-penetrating AMPK inhibitor restores MCI-i sensitivity in vivo. Lastly, our molecular analysis showed that ErbB activation is a likely mechanism of resistance to AMPK inhibition. In mouse models we will test if a brain-penetrating ErbB inhibitor overcomes AMPK inhibitor resistance in vivo.

项目摘要/摘要广泛用于管理2型糖尿病的Biguanide药物二甲双胍正在被评估为一种抗癌症试验中的肿瘤剂（NCT02780024，NCT03243851）。各种作用机理仍在研究二甲双胍作为抗肿瘤剂，但最近的研究明确表明，它在肿瘤细胞生长，细胞死亡，基因表达和信号传导中的治疗作用取决于抑制线粒体复合体I.基于二甲双胍在某些癌症中的联合疗法中的成功，新一代线粒体复合物I抑制剂（MCI-I）目前正在研究中。二甲双胍在血浆中的扩散膜发生缓慢。它的条目由两个转运蛋白Oct1和Oct2促进，在外面表达不好肝脏和肾脏。由于其在治疗浓度下缺乏在其他组织中积累的问题，因此存在问题。因此，可以利用对二甲双胍浓度较低的肿瘤亚型的鉴定用于靶向二甲双胍治疗。二甲双胍GBM试验可能不令人满意，因为没有分子标记将二甲双胍反应者与非反应者区分开。分子标记物的识别可能会大大改善 GBM中的二甲双胍和其他基于MCI-I的疗法。我们确定丙酮酸脱氢酶亚基（PDHA1）是可能在GBM中用于MCI-I治疗的分子信标。我们将在体外和体内进行测试。我们还发现细胞能量传感器AMPK在GBM的一部分中对MCI-I治疗具有抗性。我们将测试脑穿透AMPK是否抑制剂在体内恢复MCI-I敏感性。最后，我们的分子分析表明ERBB激活是一种可能的机制对AMPK抑制的抗性。在鼠标模型中，我们将测试脑渗透ERBB抑制剂是否克服AMPK 体内抑制剂抗性。