Targeting the Hedgehog Pathway in Pediatric Brain Tumors

这是一个关于HH通路在髓母细胞瘤中的作用的非常成功的项目的竞争性更新。此前，我们在自发性髓母细胞瘤小鼠模型中使用了一种HH途径的小分子拮抗剂(HhAntag)，获得了显著的结果。然而，最近我们也发现，HhAntag对幼鼠的治疗会导致严重的骨发育缺陷。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，以优化策略，为人类髓母细胞瘤的一个亚组提供这一潜在的革命性治疗。我们还将 建立新的儿童脑瘤模型，以研究HhAntag在人类髓母细胞瘤以及更广泛的儿童脑肿瘤中的作用机制。在目标1中，我们将阐述HhAntag抗肿瘤作用的机制以及它对骨发育的影响。我们将研究不同的给药方法和不同的结构类别的抑制剂，努力将对发育中的骨骼的缺失影响降至最低。我们还将筛选其他抑制物或靶点 可能对脑瘤更有选择性。在目标2中，我们建议研究微环境在体外维持HH途径活性中的作用。我们将利用干细胞培养技术，与基质支持细胞共培养，以及移植，试图保持小鼠髓母细胞瘤细胞的途径活性。一旦确定，我们将使用这些条件来繁殖携带ptch1突变的人髓母细胞瘤，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。肿瘤将被收集并通过基因组图谱进行特征描述，并用于建立新的培养和移植模型。我们将研究HhAntag在一系列肿瘤中对肿瘤和间质支持细胞的影响，包括不典型畸胎样/横纹肌样肿瘤和脉络丛癌。

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.