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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（GBM）是最具侵袭性、致命性的癌症之一，部分原因是肿瘤细胞亚群（称为脑肿瘤起始细胞（BTIC））能够抵抗当前的治疗并导致肿瘤复发。我们和其他人已经确定了 BTIC 的坏死周围生态位，该生态位与葡萄糖和其他营养物质水平降低有关。我们是第一个发现 BTIC 能够在低葡萄糖条件下生存的原因，因为葡萄糖摄取增加与葡萄糖转运蛋白 GLUT3 的升高相关。此前已知普遍表达的葡萄糖转运蛋白 GLUT1 在癌症中发挥作用，但我们的研究首次确定了这种高亲和力葡萄糖转运蛋白在 GBM 细胞中的功能作用。我们确定用 shRNA 敲低 GLUT3 可降低 BTIC 生长、神经球形成和体内致瘤潜力。尽管 GLUT1 仍然存在，但 GLUT3 shRNA 的这些表型变化与这些细胞中葡萄糖摄取的显着下降相关。由于尚无已知的 GLUT3 特异性抑制剂，并且我们的数据表明 GLUT3 抑制具有巨大益处，因此我们发起了一项合作药物发现工作。这项工作涉及基于结构的计算和药物化学研究以及生物学评估，以确定 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 生长和维持的功效，并确定它们以 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，通过改变细胞代谢来延缓肿瘤复发或治愈疾病，从而改善 GBM 治疗。