Identification of Glucose Transporter 3 Inhibitors for Glioblastoma Treatment

用于胶质母细胞瘤治疗的葡萄糖转运蛋白 3 抑制剂的鉴定

基本信息

批准号：
9284534
负责人：
CORINNE ELIZABETH AUGELLI-SZAFRAN
金额：
$ 27.26万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2016-06-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9284534
关键词：
Adult Affinity Animals Apoptosis Astrocytes Biological Biological Assay Brain Neoplasms Breast Cancer Biology Cell Differentiation process Cell Maintenance Cell Survival Cells Colon Computer Assisted Computing Methodologies Crystallization Data Differentiation Antigens Disease Drug Design Evaluation Foundations Funding Mechanisms Future GLUT-3 protein Glioblastoma Glucose Glucose Transporter Glycolysis Growth Human In Vitro Libraries Ligand Binding Ligands Lung Maintenance Malignant Neoplasms Messenger RNA Metabolic Metabolism Molecular Conformation Molecular Models Necrosis Nutrient Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Play Preclinical Testing Primary Brain Neoplasms Publishing Radio Recurrence Role SLC2A1 gene Specificity Structural Models Structure Structure-Activity Relationship Therapeutic Therapeutic Agents Therapeutic Intervention Time Toxic effect Transportation Treatment Failure Tumor Initiators Tumorigenicity Xenograft procedure base cell growth chemical synthesis chemotherapy computational chemistry design drug discovery glucose uptake high reward high risk improved in vitro Assay in vivo inhibitor/antagonist knock-down molecular dynamics molecular modeling neoplastic cell novel novel therapeutic intervention nutrient deprivation outcome forecast overexpression physiologic model preclinical trial prevent public health relevance screening small hairpin RNA small molecule therapeutic target therapy resistant tumor tumor heterogeneity tumorigenic virtual

项目摘要

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) are one of the most aggressive, deadly cancers due in part to the ability of a subset of tumor cells, called brain tumor initiating cells (BTICs), to resist current treatments and cause tumor recurrence. We and others have identified a perinecrotic niche for BTICs which is associated with reduced levels of glucose and other nutrients. We were the first to find that BTICs were able to survive low glucose conditions due to increased glucose uptake that was associated with elevation of the glucose transporter GLUT3. The ubiquitiously expressed glucose transporter GLUT1 was previously known to play a role in cancer, but our study was the first to determine a functional role for this high affinity glucose transporter in GBM cells. We determined that knockdown of GLUT3 with shRNA decreased BTIC growth, neurosphere formation, and tumorigenic potential in vivo. These phenotypic changes with GLUT3 shRNA correlated with a significant decrease in glucose uptake in these cells even though GLUT1 was still present. As there are no known GLUT3 specific inhibitors and our data suggested strong benefit for GLUT3 inhibition, we initiated a collaborative drug discovery effort. This effort involved structure-based computationa and medicinal chemistry studies and biological evaluations to identify GLUT3 selective inhibitors. We have identified two candidate compounds and will continue to evaluate the efficacy of candidate GLUT3 inhibitors against BTIC growth and maintenance and determine their ability to inhibit glucose uptake in a GLUT3 dependent manner. This study is likely to establish a new therapeutic strategy to improve GBM treatment by altering cellular metabolism to delay tumor recurrence or cure the disease.

描述（由申请人提供）：胶质母细胞瘤（GBMS）是最具侵略性，致命的癌症之一，部分原因是肿瘤细胞的能力，称为脑肿瘤启动细胞（BTICS），可抵抗当前治疗并引起肿瘤复发。我们和其他人已经确定了btics的核酸菌群小裂，这与葡萄糖和其他养分水平降低有关。我们是第一个发现BTICS能够由于葡萄糖摄取增加而能够在低葡萄糖条件下生存，这与葡萄糖转运蛋白Glut3的升高有关。众所周知，普遍表达的葡萄糖转运蛋白glut1在癌症中起作用，但我们的研究是第一个确定GBM细胞中这种高亲和葡萄糖转运蛋白的功能作用的研究。我们确定在shRNA中敲低glut3会降低BTIC生长，神经球的形成和体内肿瘤潜能。这些与GLUT3 shRNA的表型变化与这些细胞中葡萄糖摄取的显着降低相关，即使GLUT1仍然存在。由于没有已知的GLUT3特异性抑制剂，我们的数据表明对GLUT3抑制作用有很大的好处，因此我们开始了协作药物发现工作。这项工作涉及基于结构的计算和药物化学研究和生物学评估，以鉴定GLUT3选择性抑制剂。我们已经确定了两种候选化合物，并将继续评估候选GLUT3抑制剂对BTIC生长和维持的疗效，并确定其以GLUT3依赖性方式抑制葡萄糖摄取的能力。这项研究可能会建立一种新的治疗策略来通过改变细胞代谢来延迟肿瘤复发或治愈疾病来改善GBM治疗。