Targeting cancer stem cells for brain tumor therapy

靶向癌症干细胞进行脑肿瘤治疗

• 批准号: 7585750
• 负责人: John S Yu
• 金额: $ 21.94万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-12 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585750
• 关键词: Accounting; Address; Adult; Apoptosis; Area; Autologous; Biology; Bone Marrow; Brain; Brain Neoplasms; CXCR4 Receptors; CXCR4 gene; Cell Proliferation; Cell membrane; Cell physiology; Cells; Characteristics; Clinical; Conditioned Culture Media; Cytotoxic T-Lymphocytes; Drug Delivery Systems; Engraftment; Glial Fibrillary Acidic Protein; Glioblastoma; Glioma; Goals; Human; Implant; In Vitro; Investigation; Lead; Malignant Glioma; Methods; Migration Assay; Modeling; Mus; NOD/SCID mouse; National Institute of Neurological Disorders and Stroke; Nature; Phenotype; Plant Roots; Primary Brain Neoplasms; Primary Neoplasm; Progress Review Group; Proliferating; Radiosurgery; Refractory; Source; Stem cells; Testing; Therapeutic; Therapeutic Agents; Translating; Transplantation; Tropism; Tumor Biology; Tumor Cell Line; Xenograft Model; base; cancer stem cell; cell motility; chemotherapy; cytotoxic; fetal; glioma cell line; implantation; improved; in vivo; migration; neoplastic cell; nerve stem cell; new therapeutic target; novel strategies; progenitor; response; self-renewal; targeted delivery; therapeutic gene; therapeutic protein; tumor; tumor xenograft; vector

DESCRIPTION (provided by applicant): The capacity of neural stem cells (NSC) to migrate toward pathological areas of the brain underscores the potential use of these cells as agents for cell replacement and/or drug delivery in the brain. Malignant gliomas consist of cancer stem cells (CSC), which have been demonstrated recently as the roots of the tumor, being refractory to current employed therapies. We have described the efficacy of using primary murine fetal NSC or bone marrow-derived neural stem cells (BM-NSC) as delivery vehicles for cytotoxic or immunostimulatory agents to treat infiltrating glioma and have described a mechanism of glioma tropism. However, these studies were based on tumor models established with glioma cell lines. Increasing evidence indicates that primary tumor cells are necessary and better than tumor cell lines for studying tumor biology and therapeutic strategies. We have recently demonstrated that primary human glioblastomas contain CSCs. The CSCs have characteristics of self-renewal, are multipotential in vitro, and can initiate brain tumors in vivo, recapitulating the phenotypes of the primary tumors from which they were derived. We also found that BM-NSCs can migrate toward CSCs in vitro and CSCs initiated tumors in vivo. These findings lead us to pursue further studies with adult BM-NSCs as a viable source of cellular vectors to target brain tumor CSCs and deliver therapy. We now aim to test the hypotheses that: 1) BM-NSC migration toward CSCs of primary brain tumors is dependent on CXCR4 expression on the plasma membrane of BM-NSCs. 2) BM-NSC migration toward brain tumor CSCs is mainly due to GFAP+ and A2B5+ astrocytic precursors, while terminal differentiation favors engraftment of BM-NSC after intracranial transplantation. 3) Targeting CSCs with BM-NSCs can (i) translate into targeted delivery of therapeutic genes and (ii) increase tumor control and prolong survival in a CSC xenograft model. Brain tumors are among the most devastating tumors and are often rapidly fatal despite aggressive treatments. Brain tumor cancer stem cells identified from human brain tumors have the exclusive ability to drive tumor formation, and could prove an effective target for tumor therapy. In this proposal, we will develop therapeutic strategies that are effectively targeting cancer stem cells and will ultimately yield new approaches to treat brain tumors.

描述(申请人提供)：神经干细胞(NSC)向大脑病理区域迁移的能力突显了这些细胞作为细胞替代和/或脑内药物输送媒介的潜在用途。恶性胶质瘤由肿瘤干细胞(CSC)组成，最近被证明是肿瘤的根源，对目前采用的治疗方法无效。我们描述了使用原代小鼠胚胎神经干细胞或骨髓源性神经干细胞(BM-NSC)作为细胞毒或免疫刺激药物的载体治疗浸润性胶质瘤的疗效，并描述了胶质瘤趋向性的机制。然而，这些研究是基于用胶质瘤细胞系建立的肿瘤模型。越来越多的证据表明，原代肿瘤细胞是研究肿瘤生物学和治疗策略所必需的，而且优于肿瘤细胞系。我们最近证明了原发的人类胶质母细胞瘤含有CSCs。CSCs具有自我更新的特性，在体外具有多潜能，可以在体内启动脑肿瘤，概括了它们起源的原发肿瘤的表型。我们还发现，BM-NSCs在体外可以向CSCs迁移，而CSCs在体内可以启动肿瘤。这些发现引导我们进一步研究成人BM-NSCs，将其作为靶向脑肿瘤CSCs和提供治疗的细胞载体的可行来源。我们现在的目的是验证假设：1)BM-NSC向CSCs的迁移依赖于BM-NSCs质膜上CXCR4的表达。2)BM-NSC向脑肿瘤CSCs的迁移主要来源于GFAP+和A2B5+星形胶质细胞前体，而终末分化有利于BM-NSC在颅脑移植后的植入。3)在CSC异种移植模型中，BM-NSCs靶向CSCs可以(I)转化为靶向治疗基因，(Ii)增加肿瘤控制和延长存活时间。脑瘤是最具破坏性的肿瘤之一，尽管进行了积极的治疗，但往往很快就会致命。从人脑肿瘤中鉴定出的脑瘤干细胞具有独特的驱动肿瘤形成的能力，可能被证明是肿瘤治疗的有效靶点。在这项提案中，我们将开发有效针对癌症干细胞的治疗策略，并最终产生治疗脑瘤的新方法。