Generation of tumor stem cell lines for directed therapeutics of brain cancer

用于脑癌定向治疗的肿瘤干细胞系的产生

• 批准号: 7847999
• 负责人: ELVA D DIAZ
• 金额: $ 230.3万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847999
• 关键词: Adverse effects; Aftercare; Applications Grants; Brain; Brain Neoplasms; Cancer Etiology; Cancerous; Cell Line; Cells; Central Nervous System Neoplasms; Cessation of life; Chemicals; Child; Childhood Brain Neoplasm; Complex; Defect; Development; Embryo; Generations; Goals; Growth; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Outcome; Phenotype; Population; Primary Brain Neoplasms; Property; Quality of life; Radiation therapy; Recurrence; Resistance; Somatic Cell; Survivors; Therapeutic; Tumor Stem Cells; United States; abstracting; cell transformation; cellular targeting; induced pluripotent stem cell; innovation; medulloblastoma; neoplastic cell; nerve stem cell; novel strategies; novel therapeutics; public health relevance; retroviral-mediated; stem; transcription factor; tumor; tumorigenic

DESCRIPTION (Provided by the applicant) Abstract: Tumors of the central nervous system (CNS) comprise nearly one quarter of all childhood cancers. Although progress has been made in the treatment of some types of childhood cancer, the outcome for children with primary CNS tumors has remained bleak and little advancement has been made in the last decade. In addition, due to the adverse effects of the tumor on brain development or the treatment required to control its growth, survivors of childhood brain tumors often have severe neurodevelopmental defects that negatively impact their quality of life. Thus, there is a need for better treatments specific for childhood brain tumors. Current models suggest that only a few atypical cells within the cancerous mass are responsible for the initiation, growth and recurrence of brain tumors. These transformed cells have both the defining properties of neural stem cells and the ability to initiate cancer - thus, these cells are referred to as 'brain tumor stem (BTS) cells'. While the isolation of neural stem cells is fairly well established, the isolation of BTS cells remains a difficult and complex issue, suggesting the need for innovative approaches to isolate and characterize these cells. The development of induced pluripotent stem cells (somatic cells that have been reprogrammed to an embryonic-like pluripotent state by retroviral-mediated introduction of specific transcription factors) represents a powerful new approach that might alleviate such confounding issues. Thus, the goals of the proposed project are: 1) to reprogram brain tumor cells towards a more stem-like phenotype; 2) to characterize the tumorigenic potential of such reprogrammed tumor stem-like cell lines; and 3) to identify chemical compounds that specifically target the reprogrammed tumor stem-like cells. Completion of these studies will provide a directed strategy for novel therapeutics to specifically target the cellular population responsible for the initiation, growth and recurrence of pediatric brain tumors. Public Health Relevance: Brain tumors are the second leading cause of cancer-related death in children in the United States and medulloblastoma is the most common pediatric brain tumor. An increasing amount of evidence suggests that only a few atypical cells (brain tumor stem cells) within the cancerous mass are responsible for the initiation, growth and recurrence of primary brain tumors. Brain tumor stem cells appear to be resistant to traditional chemo- and radiation therapies compared with the more differentiated cells in the cancerous mass, suggesting a mechanism underlying tumor recurrence after treatment. Thus, the focus of the present grant proposal is to generate stable brain tumor stem cell lines and to identify chemical compounds that specifically target the reprogrammed tumor stem-like cells

描述(由申请人提供) 摘要：中枢神经系统肿瘤占儿童癌症的近四分之一。尽管在治疗某些类型的儿童癌症方面取得了进展，但患有原发中枢神经系统肿瘤的儿童的结果仍然黯淡，在过去十年中几乎没有取得进展。此外，由于肿瘤对大脑发育的不利影响或控制其生长所需的治疗，儿童脑瘤幸存者往往有严重的神经发育缺陷，对他们的生活质量产生负面影响。因此，有必要针对儿童脑瘤进行更好的治疗。目前的模型表明，只有癌变肿块中的少数非典型细胞对脑瘤的起始、生长和复发负责。这些转化后的细胞既具有神经干细胞的特性，又具有启动癌症的能力--因此，这些细胞被称为“脑瘤干细胞(BTS)”。虽然神经干细胞的分离已经相当成熟，但BTS细胞的分离仍然是一个困难和复杂的问题，这表明需要创新的方法来分离和鉴定这些细胞。诱导多能干细胞(通过逆转录病毒介导的特定转录因子的导入，已被重新编程为类似胚胎的多能状态的体细胞)的发展代表了一种强大的新方法，可能会缓解这种混乱的问题。因此，拟议项目的目标是：1)将脑肿瘤细胞重新编程为更具干细胞样表型；2)表征这种重新编程的肿瘤干细胞系的致瘤潜力；以及3)鉴定专门针对重新编程的肿瘤干细胞的化合物。这些研究的完成将为新的治疗方法提供一种定向策略，专门针对负责儿童脑肿瘤的起始、生长和复发的细胞群体。 公共卫生相关性：脑瘤是美国儿童癌症相关死亡的第二大原因，髓母细胞瘤是最常见的儿童脑肿瘤。越来越多的证据表明，只有癌变肿块中的少数非典型细胞(脑肿瘤干细胞)与原发脑肿瘤的发生、生长和复发有关。与癌块中分化较多的细胞相比，脑肿瘤干细胞似乎对传统的化疗和放射治疗具有抵抗力，这表明治疗后肿瘤复发的机制。因此，目前拨款提案的重点是建立稳定的脑瘤干细胞系，并鉴定专门针对重新编程的肿瘤干细胞样细胞的化合物。