Screening for modulators of glioma stem cells differentiation

神经胶质瘤干细胞分化调节剂的筛选

基本信息

批准号：
8605810
负责人：
BAKHOS A TANNOUS
金额：
$ 34.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605810
关键词：
Accounting Acids Adult Affect American Area Automobile Driving Behavior Biological Biological Assay Biological Process Bioluminescence Blood Brain Cell Proliferation Cell Survival Cell model Cell physiology Cells Central Nervous System Neoplasms Cessation of life Clinical Trials Codon Nucleotides Complementary DNA Complex Conditioned Culture Media Cultured Cells Differentiation Inducer Elements Engineering Enzymes Fireflies Gene Expression Gene Transfer Genes Genetic Transcription Glial Fibrillary Acidic Protein Glioblastoma Glioma Human Laboratories Light Luciferases Luciola Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Nude Mice Ostracods Patients Pharmaceutical Preparations Phenocopy Preclinical Drug Evaluation Recurrence Renilla Reporter Reporting Resected Resistance Simian virus 40 Stem cells Stromal Cells Subfamily lentivirinae System Tandem Repeat Sequences Testing Time Tretinoin Validation Variant Western Blotting Xenograft procedure base cancer stem cell clinically relevant coelenterazine conventional therapy drug discovery high throughput screening in vivo internal control luciferin neoplastic cell novel pre-clinical promoter public health relevance screening self-renewal stem cell differentiation thermostability tool tumor

项目摘要

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.

描述（由申请人提供）：神经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。胶质母细胞瘤具有高度异质性，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备重现原始肿瘤表型的能力，并且肿瘤中只有一小部分细胞（称为癌症干细胞）在裸鼠异种移植后具有这种能力。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物，要么导致分化程度更高的细胞恢复类似干细胞的行为。与非癌症干细胞相比，这些癌症干细胞似乎对常规疗法更具抵抗力。在目前对高级别神经胶质瘤的治疗之后，大多数患者在一年内死于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，它们很可能是与肿瘤复发有关。旨在根除神经胶质瘤干细胞或将这些细胞恢复到更加分化的状态（然后可以对常规疗法做出反应）的靶向疗法非常有益，并且目前正在使用全反式视黄酸进行临床试验（ATRA；://clinicaltrials） .gov）。在本提案中，我们将优化用于高通量筛选的三重分泌报告系统，并用它来寻找神经胶质瘤干细胞的调节剂。我们将同时筛选具有以下功能的药物：（1）将胶质母细胞瘤干细胞恢复到更加分化的状态，使它们对常规疗法敏感； (2)消灭这些细胞。然后，我们将在颅内神经胶质瘤干细胞模型中分析潜在的药物效果，该模型会像人类肿瘤一样渗透到小鼠的大脑中。