Identification of Glucose Transporter 3 Inhibitors for Glioblastoma Treatment

描述(申请人提供)：胶质母细胞瘤(GBM)是最具侵袭性、最致命的癌症之一，部分原因是一种称为脑肿瘤启动细胞(BTIC)的肿瘤细胞亚群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BTICs的坏死区，这与葡萄糖和其他营养物质水平的降低有关。我们是第一个发现BTIC能够在低糖条件下存活的原因是葡萄糖摄取增加，这与葡萄糖转运蛋白GLUT3的升高有关。此前，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敲除GLUT3会减少BTIC的生长、神经球的形成和体内的致瘤潜力。GLUT3shRNA的这些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。由于目前还没有已知的GLUT3特异性抑制剂，而且我们的数据显示对抑制GLUT3有很大的好处，我们发起了一项合作的药物发现工作。这项工作涉及基于结构的计算、药物化学研究和生物学评估，以确定GLUT3选择性抑制剂。我们已经确定了两个候选化合物，并将继续评估候选GLUT3抑制剂对BTIC生长和维持的有效性，并确定它们以GLUT3依赖的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这种疾病，从而改善GBM的治疗。

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.