Targeting the Hedgehog Pathway in Pediatric Brain Tumors

靶向小儿脑肿瘤中的 Hedgehog 通路

• 批准号: 8459558
• 负责人: TOM CURRAN
• 金额: $ 34.41万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459558
• 关键词: Address; Adult; Adverse effects; Affect; Bone Development; Brain; Brain Neoplasms; Cell Culture Techniques; Cell Line; Cell Transplantation; Cells; Child; Childhood; Childhood Brain Neoplasm; 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; Neoplasms; 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; tumor microenvironment

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.

这是一个非常成功的项目的竞争性更新，该项目涉及 Hh 通路在髓母细胞瘤中的作用。此前，我们在自发性髓母细胞瘤小鼠模型中使用 Hh 通路小分子拮抗剂 (HhAntag) 获得了显着的结果。然而，最近我们还发现，HhAntag 治疗幼鼠会导致骨骼发育严重缺陷。我们现在将研究 HhAntag 在肿瘤细胞以及骨骼发育中的作用机制，以优化为人类髓母细胞瘤亚型提供这种潜在革命性治疗的策略。我们还将 建立新的儿科脑肿瘤模型，以研究 HhAntag 在人髓母细胞瘤以及更广泛的儿科脑肿瘤中的作用机制。在目标 1 中，我们将探讨 HhAntag 的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结构类别的抑制剂，以尽量减少对骨骼发育的有害影响。我们还将筛选其他抑制剂或靶标 可能对脑肿瘤更具选择性。在目标 2 中，我们建议研究微环境在体外维持 Hh 通路活性中的作用。我们将利用干细胞培养技术、与基质支持细胞共培养以及移植，试图维持小鼠髓母细胞瘤细胞的通路活性。一旦建立，我们将利用这些条件来繁殖携带 PTCH1 突变的人类髓母细胞瘤，以便我们可以测试它们对 HhAntag 的反应。在目标 3 中，我们将研究 Hh 通路在缺乏已知 Hh 通路突变的儿童脑肿瘤中的作用。 将收集肿瘤并通过基因组分析进行表征，并用于建立新的培养和移植模型。我们将研究 HhAntag 对一系列肿瘤中的肿瘤和基质支持细胞的影响，包括非典型畸胎瘤/横纹肌样瘤和脉络丛癌。