Targeting the Hedgehog Pathway in Pediatric Brain Tumors

这是一个非常成功的项目的竞争性更新，该项目涉及HH途径在 髓母细胞瘤。此前，我们使用一种HH的小分子拮抗剂获得了显著的结果 自发性髓母细胞瘤小鼠模型中的途径(HhAntag)。但是最近我们也发现， 对幼鼠进行HhAntag治疗会导致骨骼发育严重缺陷。我们现在要调查 HhAntag在肿瘤细胞和骨骼发育中的作用机制，以优化治疗策略 为人类髓母细胞瘤的一个子集提供这种潜在的革命性治疗方法。我们还将 建立新的儿童脑瘤模型研究HhAntag对人的作用机制 髓母细胞瘤以及更广泛的儿童脑肿瘤。在目标1中，我们将解决 HhAntag抗肿瘤作用机制及其对骨发育的影响。我们 将研究替代给药方法和不同结构类别的抑制剂，以努力 最大限度地减少对骨骼发育的影响。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，我们建议调查 体外维持HH途径活性的微环境。我们将利用干细胞培养技术，共培养 使用基质支持细胞，并进行移植以试图保持小鼠的通路活性 髓母细胞瘤细胞。一旦确定，我们将利用这些条件来繁殖人类 髓母细胞瘤携带ptch1突变，因此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表征，并用于建立新的培养和 移植模型。我们将研究HhAntag对小鼠肿瘤和基质支持细胞的影响。 肿瘤的范围，包括不典型的畸胎样/横纹肌样瘤和脉络丛癌。

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.