Identification of Glucose Transporter 3 Inhibitors for Glioblastoma Treatment

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））具有抵抗当前治疗并导致肿瘤复发的能力。 我们和其他人已经确定了BTIC的围坏死生态位，这与葡萄糖和其他营养物质水平的降低有关。 我们首先发现BTIC能够在低葡萄糖条件下存活，这是由于葡萄糖摄取增加，这与葡萄糖转运蛋白GLUT 3的升高有关。 以前已知泛在表达的葡萄糖转运蛋白GLUT1在癌症中发挥作用，但我们的研究是第一个确定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。 GLUT3 shRNA的这些表型变化与这些细胞中葡萄糖摄取的显著减少相关，即使GLUT1仍然存在。 由于没有已知的GLUT3特异性抑制剂，并且我们的数据表明GLUT3抑制具有很强的益处，因此我们启动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和生物学评价，以确定GLUT 3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GLUT 3抑制剂对BTIC生长和维持的疗效，并确定其以GLUT 3依赖性方式抑制葡萄糖摄取的能力。 该研究可能建立一种新的治疗策略，通过改变细胞代谢来改善GBM治疗，以延迟肿瘤复发或治愈疾病。

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.