Targeting the Hedgehog Pathway in Pediatric Brain Tumors

这是一个高度成功的项目有关的Hh通路在髓母细胞瘤中的作用的竞争更新。以前，我们获得了戏剧性的结果，使用Hh通路的小分子拮抗剂（HhAntag）在一个自发的小鼠髓母细胞瘤模型。然而，最近，我们也发现HhAntag治疗年轻小鼠会导致骨骼发育严重缺陷。我们现在将研究HhAntag在肿瘤细胞中的作用机制，以及在骨发育中的作用机制，以优化为人类髓母细胞瘤亚群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，我们将讨论HhAntag的抗肿瘤作用机制以及其对骨发育的影响。我们将研究替代的传递方法和不同结构类别的抑制剂，以尽量减少对发育中的骨的有害影响。我们还将筛选其他抑制剂或靶点， 可能对脑肿瘤更有选择性。在目的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，并移植，试图维持小鼠髓母细胞瘤细胞的通路活性。一旦建立，我们将使用这些条件来繁殖携带PTCH 1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。 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作用，包括非典型畸胎瘤/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.