Glioblastoma stem cells therapy

摘要 神经胶质瘤占所有原发性CNS肿瘤的约60%。胶质母细胞瘤（GBM）或IV级胶质瘤， 占所有胶质瘤的50.9%，是最恶性的形式。胶质母细胞瘤肿瘤是高度异质性的 并且在肿瘤内不同类型的肿瘤细胞和基质细胞之间存在复杂的相互作用。 最近研究表明，大多数肿瘤细胞没有重演肿瘤细胞凋亡的能力。 表型复制的原始肿瘤，只有一个小的细胞亚群在肿瘤中，称为癌症干细胞 细胞在裸鼠中异种移植时具有这种能力。这些癌症干细胞似乎比 与非癌症干细胞相比，它们对常规疗法如化疗和放疗具有抗性。 在目前治疗高级别胶质瘤后，大多数患者在一年内死于新的继发性胶质瘤。 肿瘤病灶在切除区域的一厘米内形成。这些病灶富含癌症干细胞， 并且它们很可能是肿瘤复发的原因。我们的建议侧重于确定小 分子药物，可以增加GBM干细胞的治疗效果。肿瘤坏死因子相关 肿瘤坏死诱导配体（TRAIL）被认为是一种潜在的抗癌药物。然而，相当多的 许多不同类型的癌细胞，包括GBM，对TRAIL诱导的凋亡具有抗性。我们 他们计划鉴定候选药物，这些药物可以直接杀死原代GBM干细胞，也可以使这些细胞敏感， TRAIL诱导的细胞凋亡。我们将使用我们开发的高通量细胞凋亡筛选试验 基于天然分泌的Gaussia荧光素酶，筛选不同的小分子文库， 含有FDA批准的能穿过血脑屏障的药物我们将验证最有希望的 在我们的实验性胶质瘤干细胞体内生物发光模型中的药物命中。

Abstract Gliomas account for about 60% of all primary CNS tumors. Glioblastoma (GBM) or grade IV gliomas which comprise 50.9% of all gliomas are the most malignant form. Glioblastoma tumors are highly heterogeneous and there is a complex interaction among different types of tumor cells and stromal cells within the tumor. Recently it has been shown that the majority of tumor cells do not have the capacity to recapitulate a phenocopy of the original tumor and that only a small subpopulation of cells in the tumor, called cancer stem cells, have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy, like chemotherapy and radiation, as compared to the non-cancer stem cells. Following current therapy for high-grade glioma tumors, most patients die within a year from a new secondary tumor foci forming within one centimeter of the resected area. These foci are enriched for cancer stem cells, and it is likely that they are responsible for tumor recurrence. Our proposal focuses on identifying small molecule drugs which can increase therapeutic efficacy for GBM stem cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anti-cancer agent. However, a considerable number of different types of cancer cells, including GBM, are resistant to apoptosis induction by TRAIL. We plan to identity drug candidates which either kill primary GBM stem cells directly or can sensitize these cells to TRAIL-induced apoptosis. We will use a high throughput apoptosis-screening assay which we have developed based on the naturally secreted Gaussia luciferase and screen different small molecule libraries including ones containing FDA-approved drugs which crosses the blood-brain barrier. We will validate the most promising drug hits in our experimental glioma stem cells-bioluminescent model in vivo.