Screening for modulators of glioma stem cells differentiation

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。最近已经表明，大多数肿瘤细胞不具有重现原始肿瘤的表型的能力，并且肿瘤中只有一小部分细胞亚群（称为癌症干细胞）在裸鼠中异种移植时具有这种能力。根据癌症干细胞假说，癌症中的分子改变要么将正常干细胞转化为异常对应物，要么导致分化程度更高的细胞恢复干细胞样行为。与非癌症干细胞相比，这些癌症干细胞似乎对常规治疗更具抵抗力。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。这些病灶富含癌症干细胞，并且很可能是 导致肿瘤复发。旨在根除神经胶质瘤干细胞或将这些细胞恢复到可随后响应于常规疗法的更分化状态的靶向疗法是高度有益的，并且目前正在使用全反式视黄酸的临床试验中进行测试（ATRA;：clinicaltrials.gov）。在这个建议中，我们将优化一个三重分泌报告系统的高通量筛选，并使用它来寻找神经胶质瘤干细胞的调节剂。我们将同时筛选药物，这些药物可以：（1）将胶质母细胞瘤癌症干细胞恢复到更分化的状态，使它们对常规治疗敏感;（2）根除这些细胞。然后将在颅内神经胶质瘤干细胞模型中分析潜在的药物命中，该模型浸润小鼠的大脑，类似于人类肿瘤。

DESCRIPTION (provided by applicant): 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. According to the cancer stem cell hypothesis, molecular alterations in cancer either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert towards a stem cell-like behavior. These cancer stem cells appear to be more resistant to conventional therapy, 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. Targeted therapies aiming at eradication of glioma stem cells, or reverting these cells into a more differentiated state which can then responds to conventional therapy is highly beneficial and are current being tested in clinical trials using all-trans retinoc acids (ATRA; ://clinicaltrials.gov). In this proposal, we will optimize a triple secreted reporter system for high-throughput screening and use it to find modulators of glioma stem cells. We will simultaneously screen for drugs which either: (1) revert glioblastoma cancer stem cells into a more differentiated state, making them susceptible to conventional therapy; (2) eradicate these cells. Potential drug hits will then be analyzed in an intracranial glioma stem cells model which infiltrates the brain of mice similar to human tumors.