Targeting the Hedgehog Pathway in Pediatric Brain Tumors

靶向小儿脑肿瘤中的 Hedgehog 通路

• 批准号: 8056128
• 负责人: TOM CURRAN
• 金额: $ 51.94万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8056128
• 关键词: Address; Adult; Adverse effects; Affect; Bone Development; Brain Neoplasms; Carcinoma; Cell Culture Techniques; Cell Line; Cell Transplantation; Cells; Child; Childhood; Childhood Brain Neoplasm; Choroid; Choroid Plexus Carcinoma; Coculture Techniques; Defect; Development; Disease; Dose; Epigenetic Process; Erinaceidae; Exhibits; Funding; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Growth; Human; In Vitro; Malignant Glioma; Methods; Modeling; Mus; Mutation; Pathway interactions; Population; Rhabdoid Tumor; Role; Sampling; Series; Stem cells; Stromal Cells; Stromal Neoplasm; Supporting Cell; System; Testing; Transplantation; Transplantation Conditioning; Tumor Cell Line; Tumor-Derived; Work; Xenograft procedure; bone; cancer stem cell; cancer therapy; cell growth; design; drug discovery; improved; in vitro activity; in vivo; inhibitor/antagonist; medulloblastoma; mouse model; neoplastic cell; novel strategies; patient population; response; small molecule; tumor

This is a competing renewal of a highly succesful project concerning the role of the Hh pathway in medulloblastoma. Previously, we obtained dramatic results using a small molecule antagonist of the Hh pathway (HhAntag) in a spontaneous mouse model of medulloblastoma. However, recently, we also found that HhAntag treatment of young mice causes severe defects in bone development. We will now investigate the mechanism of action of HhAntag in tumor cells, as well as in developing bone, to optimize strategies for delivering this potentially revolutionary treatment for a subset of human medulloblastoma. We will also establish new pediatric brain tumor models to investigate the mechanism of action of HhAntag in human medulloblastoma as well as in a broader spectrum of pediatric brain tumors. In Aim 1, we will address the mechanism responsible for the anti-tumor effect of HhAntag as well as its effect on bone development. We will investigate alternative delivery methods and different structural classes of inhibitors in an effort to minimize the deletrious effects on developing bone. We will also screen for other inhibitors or targets that may be more selective for brain tumors. In Aim 2, we propose to investigate the role of the microenvironment in maintaining Hh pathway activity in vitro. We will utilize stem cell culture techniques, coculture with stromal support cells, and transplantation in an attempt to maintain pathway activity in mouse medulloblastoma cells. Once established, we will use these conditions to propagate human medulloblastoma carrying PTCH1 mutations so that we can test their response to HhAntag. In Aim 3, we will investigate the role of the Hh pathway in pediatric brain tumors lacking known Hh pathway mutations. Tumors will be collected and characterized by genomic profiling, and used to establish new culture and transplantation models. We will investigate the effect of HhAntag on tumors and stromal support cells in a range of tumors, including Atypical Teratoid/Rhabdoid Tumors and Choroid Plexus Carcinoma.

这是对HH途径在 髓母细胞瘤。以前，我们使用了HH的小分子拮抗剂获得了戏剧性的结果 髓母细胞瘤自发小鼠模型中的途径（hhantag）。但是，最近，我们也发现了 hhantag对年轻小鼠的治疗会导致骨发育中的严重缺陷。我们现在将调查 Hhantag在肿瘤细胞以及发育骨骼中的作用机理，以优化策略 为人类髓母细胞瘤的一部分提供了这种潜在的革命治疗方法。我们也会 建立新的小儿脑肿瘤模型来研究Hhantag在人类中的作用机理 髓母细胞瘤以及较广泛的小儿脑肿瘤。在AIM 1中，我们将解决 负责Hhantag抗肿瘤作用及其对骨骼发育的影响的机制。我们 将研究替代的递送方法和不同的结构类别的抑制剂，以便 最大程度地减少对发育骨骼的缺陷影响。我们还将筛选其他抑制剂或目标 可能对脑肿瘤更具选择性。在AIM 2中，我们建议调查 在体外维持HH途径活性方面的微环境。我们将利用干细胞培养技术，共培养 用基质支持细胞和移植以维持小鼠的途径活性 髓母细胞瘤细胞。建立后，我们将利用这些条件来传播人类 携带PTCH1突变的髓母细胞瘤，以便我们可以测试其对Hhantag的反应。在AIM 3中，我们将 研究HH途径在缺乏已知HH途径突变的小儿脑肿瘤中的作用。 肿瘤将以基因组分析收集和特征，并用于建立新的培养物和 移植模型。我们将研究Hhantag对A中肿瘤和基质支持细胞的影响 肿瘤的范围，包括非典型霉菌/牙龈肿瘤和脉络膜癌。