Targeting the Hedgehog Pathway in Pediatric Brain Tumors

靶向小儿脑肿瘤中的 Hedgehog 通路

基本信息

批准号：
8243626
负责人：
TOM CURRAN
金额：
$ 52.74万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
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/8243626
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

项目摘要

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途径在髓母细胞瘤中的作用的高度成功项目的竞争更新。以前，我们使用髓母细胞瘤自发小鼠模型中HH途径（Hhantag）的小分子拮抗剂获得了戏剧性的结果。但是，最近，我们还发现，hhantag治疗年轻小鼠会导致骨发育中的严重缺陷。现在，我们将研究Hhantag在肿瘤细胞以及发育骨骼中的作用机理，以优化为人类髓母细胞瘤的一部分提供这种革命性治疗的策略。我们也会建立新的小儿脑肿瘤模型，以研究Hhantag在人类髓母细胞瘤以及更广泛的小儿脑肿瘤中的作用机理。在AIM 1中，我们将解决负责Hhantag抗肿瘤作用的机制及其对骨骼发育的影响。我们将研究替代的递送方法和不同的结构类别的抑制剂，以最大程度地减少对发育骨骼的缺乏影响。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，我们建议研究微环境在体外保持HH途径活性中的作用。我们将利用干细胞培养技术，与基质支持细胞的共培养以及移植，以尝试维持小鼠髓母细胞瘤细胞的途径活性。建立后，我们将使用这些条件来传播携带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。肿瘤将通过基因组分析收集和特征，并用于建立新的培养和移植模型。我们将研究hhantag对肿瘤和基质支持细胞的影响，包括非典型的霉菌/色肽肿瘤和脉络膜神经癌。