Screening for modulators of glioma stem cells differentiation

描述（申请人提供）：胶质瘤约占所有原发性中枢神经系统肿瘤的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。胶质母细胞瘤肿瘤具有高度的异质性，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。最近的研究表明，大多数肿瘤细胞不具有再现原肿瘤表型的能力，只有肿瘤中的一小部分细胞（称为癌症干细胞）在裸鼠异种移植中具有这种能力。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的对应细胞，要么导致分化程度更高的细胞恢复到干细胞样行为。与非癌症干细胞相比，这些癌症干细胞似乎对传统疗法更有抵抗力。在目前的高级别胶质瘤治疗下，大多数患者在一年内死于在切除区域一厘米内形成的新的继发性肿瘤灶。这些病灶富含癌症干细胞，而且很可能是这样

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.