Glioblastoma stem cells therapy

 描述（由申请人提供）：胶质瘤约占所有原发性CNS肿瘤的60%。胶质母细胞瘤（GBM）或IV级胶质瘤占所有胶质瘤的51.2%，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，大多数肿瘤细胞不具有重现原始肿瘤表型的能力，并且肿瘤中只有一小部分神经干细胞样细胞亚群，称为神经胶质瘤干细胞（GSC;也称为肿瘤起始细胞），具有这种能力 在裸鼠中异种移植后。这些癌症干细胞与其分化的对应物相比，似乎对常规治疗更具抗性。在目前对高级别胶质瘤的治疗之后，大多数患者在一年内死于在切除区域的一厘米内形成的新的继发性肿瘤病灶。这些病灶富含GSC，并且它们可能是肿瘤复发的原因。一种新兴的癌症治疗方法是利用肿瘤细胞中的生物化学变化。肿瘤（包括GBM）存在特别高水平的氧化应激，通常由活性氧（ROS）产生的增加或细胞内ROS清除剂的减少引起。ROS的这种显著增加被认为促进细胞存活并赋予对治疗的抗性。鉴于正常细胞和肿瘤细胞之间的这种不同的氧化还原状态，据信后者更依赖于它们的ROS清除能力。因此，氧化应激的进一步增加可以压倒肿瘤细胞中的这种应激反应，导致细胞死亡。另一方面，神经胶质瘤干细胞具有比它们的非致瘤性对应物低得多的代谢状态，并且这些细胞维持低水平的ROS，这对于它们的自我更新至关重要。通过高通量筛选，我们确定了天然化合物钝角醌通过诱导细胞内高水平的ROS来杀死胶质瘤细胞。我们假设这种ROS诱导小分子可以靶向GBM细胞和GSC并杀死它们。在本提案中，我们将在培养的不同GBM和GSC以及不同GSC颅内模型中验证该化合物。

 DESCRIPTION (provided by applicant): Gliomas account for about 60% of all primary CNS tumors. Glioblastoma (GBM) or grade IV glioma which comprise 51.2% of all gliomas is 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 neural stem-like cells in the tumor, called glioma stem cells (GSCs; also known as tumor initiating cells), have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy as compared to their differentiated counterparts. 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 GSCs, and it is likely that they are responsible for tumor recurrence. An emerging cancer therapeutic approach is to exploit the biochemical changes in tumor cells. Tumors (including GBM) present particularly high levels of oxidative stress, generally caused by an increase in reactive oxygen species (ROS) production or decrease in intracellular ROS-scavengers. This marked increase in ROS is believed to promote cell survival and confer resistance to therapy. Given this different redox state between normal and tumor cells, it is believed that the latter has a greater reliance on their ROS-scavenging capacities. Thus, further increase in oxidative stress can overwhelm this stress response in tumor cells leading to cell death. On the other hand, glioma stem cells have substantially lower metabolic state than their nontumorigenic counterparts and these cells maintain low levels of ROS, essential for their self-renewal. Through high-throughput screening, we identified the natural compounds obtusaquinone to kill glioma cells by inducing high levels of intracellular ROS. We hypothesize that this ROS-inducing small molecule could target both GBM cells as well as GSCs and kill them. In this proposal, we will validate this compound on different GBM and GSCs in culture and in different GSCs intracranial models.