Inducing neural maturation in medulloblastoma by targeting EZH2

项目总结/摘要 髓母细胞瘤是最常见的小儿脑肿瘤， 所有的儿童脑瘤。髓母细胞瘤恶性度高，治疗困难，近30% 被感染的病人无法治愈此外，即使治愈的儿童也会遭受严重的长期 缺陷主要是由于放射治疗的负面影响，以不断增长和发展 孩子的大脑幸存者患有记忆力和注意力缺陷、智商、认知和学习能力下降 残疾、甲状腺和性腺功能障碍（不育）和生长迟缓。据估计，只有不到20%的 成年的髓母细胞瘤幸存者能够独立生活。因此更 对于患有髓母细胞瘤的患者，非常需要有效且毒性较小的治疗。 髓母细胞瘤由原始未分化的神经母细胞组成， 自发成熟为类似神经元分化的非增殖性脑样组织 这是正常大脑发育过程中发生的。我们假设自发性成熟是 表观遗传学驱动，并通过阐明自发成熟的驱动因素，新的治疗途径 这将使我们能够在临床上诱导成熟，并迫使恶性肿瘤进入 良性脑样组织我们发现髓母细胞瘤的成熟区和原始区具有明显的 不同的RNA表达模式，PRC 2是人体组织中这一过程的主要调节因子 样品和动物模型。 在这项提议中，我们的目标是通过探索神经发育过程来劫持MB的治疗。 自发成熟的机制，以确定由PRC 2通过以下途径调节的途径 具体目标：1）整合成熟和成熟的表观遗传机制和转录组学的分子解剖， 2）阐明EZH 2在人髓母细胞瘤的表观遗传调控中的作用， 小鼠SHH MB中的肿瘤细胞成熟，和3）评估肿瘤脉管系统的功效和毒性。 在SHH驱动的髓母细胞瘤中靶向EZH 2和Sonic hedgehog（SHH）通路抑制。我们将 利用高分辨率基因组学和表观遗传学技术， 一种重现人类疾病的模型，以及一种新型肿瘤血管特异性纳米颗粒药物 该递送平台允许穿透血脑屏障。 我们的长期目标是确定肿瘤选择性表观遗传策略， 与目前髓母细胞瘤的标准治疗方法协同作用。如果我们的结果 证明是有利的，我们设想适用于髓母细胞瘤和其他脑肿瘤患者。

Project Summary/Abstract Medulloblastoma is the most common pediatric brain tumor and accounts for approximately 20% of all brain tumors in children. Medulloblastoma is highly malignant and difficult to treat resulting in nearly 30% of affected patients being incurable. Additionally, even children that are cured suffer from severe long-term deficiencies primarily due to the negative side effects of radiation therapy to the growing and developing child's brain. Survivors suffer from memory and attention deficits, decreased IQ, cognitive and learning disabilities, thyroid and gonadal dysfunction (infertility) and growth delay. It is estimated that fewer than 20% of medulloblastoma survivors who reach adulthood are able to live independent lives. Therefore, more effective and less toxic therapies are greatly needed for patients with medulloblastoma. While medulloblastoma is composed of primitive undifferentiated neuroblasts, some tumors show foci of spontaneous maturation into a non-proliferative brain-like tissue that resembles neuronal differentiation processes that occur during normal brain development. We hypothesize that spontaneous maturation is epigenetically driven and by elucidating the drivers of spontaneous maturation, novel therapeutic avenues can be identified that will allow us to induce maturation in the clinic and force the malignant tumor into benign brain-like tissue. We show that mature and primitive areas in medulloblastoma have distinctly different RNA expression patterns and that PRC2 is a master regulator of this process in human tissue samples and animal models. In this proposal, we aim to hijack neurodevelopmental processes for therapy of MB by exploring the mechanism of spontaneous maturation to identify the pathways regulated by PRC2 through the following specific aims: 1) Integrating molecular dissection of epigenetic machinery and transcriptomics in mature and primitive components of human medulloblastoma, 2) Elucidate the role of EZH2 in epigenetic regulation of tumor cell maturation in mouse SHH MB, and 3) Assess the efficacy and toxicity of tumor vasculature- targeted EZH2 and Sonic hedgehog (SHH) pathway inhibition in SHH-driven medulloblastoma. We will utilize high resolution genomics and epigenetics techniques, a genetically relevant mouse medulloblastoma model that recapitulates the human disease, and a novel tumor vasculature-specific nanoparticle drug delivery platform that allows penetration past the blood-brain barrier. Our long-term objective is to identify tumor-selective epigenetic strategies to induce spontaneous maturation that synergize with current standard of care therapies for medulloblastoma. Should our results prove favorable, we envision applicability to patients with medulloblastoma and other brain tumors.