Inducing neural maturation in medulloblastoma by targeting EZH2

项目概要/摘要 髓母细胞瘤是最常见的小儿脑肿瘤，约占所有脑肿瘤的20 儿童肿瘤髓母细胞瘤是高度恶性和难以治疗，导致近30%的受影响 病人无法治愈。此外，即使是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对生长和发育中的儿童大脑的不良副作用。 幸存者遭受记忆力，注意力缺陷，智商下降，认知和学习障碍，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%的髓母细胞瘤 成年的幸存者可以独立生活。因此，更有效和毒性更小的治疗方法 是髓母细胞瘤患者非常需要的。 虽然髓母细胞瘤由原始未分化的神经母细胞组成，但一些肿瘤显示出 自发成熟为类似神经元分化过程的非增殖性脑样组织 在正常的大脑发育过程中。我们假设自发成熟是由表观遗传驱动的， 阐明自发成熟的驱动因素，可以确定新的治疗途径， 在临床上可诱导肿瘤成熟，迫使恶性肿瘤向良性脑样组织生长。我们证明了 髓母细胞瘤成熟区和原始区的RNA表达模式明显不同， PRC 2是人体组织样品和动物模型中该过程的主要调节剂。 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）评估肿瘤血管靶向的化疗的功效和毒性。 EZH 2和Sonic Hedgehog（SHH）通路抑制SHH驱动的髓母细胞瘤。我们将利用高- 分辨率基因组学和表观遗传学技术，遗传相关的小鼠髓母细胞瘤模型， 概述了人类疾病，以及一种新的肿瘤血管特异性纳米颗粒药物递送平台 可以穿透血脑屏障 我们的长期目标是确定肿瘤选择性表观遗传策略，以诱导自发成熟 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 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 adverse side effects of radiation therapy on the growing and developing child's brain. Survivors suffer from memory, 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 can 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 resembling neuronal differentiation processes during normal brain development. We hypothesize that spontaneous maturation is epigenetically driven; 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 the current standard of care therapies for medulloblastoma. Should our results prove favorable, we envision applicability to patients with medulloblastoma and other brain tumors.