Inducing neural maturation in medulloblastoma by targeting EZH2

项目摘要/摘要 髓母细胞瘤是最常见的儿童脑肿瘤，约占所有脑肿瘤的20%。 儿童肿瘤。髓母细胞瘤恶性程度很高，很难治疗，导致近30%的患者 病人是不治之症。此外，即使治愈的儿童也患有严重的长期缺乏症。 主要是由于放射治疗对生长发育中的儿童大脑的不良副作用。 幸存者患有记忆力、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(不育症)和生长迟缓。据估计，只有不到20%的髓母细胞瘤 成年后的幸存者可以独立生活。因此，更有效和毒性更低的治疗方法 对于髓母细胞瘤患者来说是非常需要的。 虽然髓母细胞瘤是由原始的未分化神经母细胞组成的，但一些肿瘤表现为 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。我们假设自然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，使 US在临床上诱导成熟，迫使恶性肿瘤转化为良性脑样组织。我们证明了 髓母细胞瘤的成熟区和原始区具有明显不同的RNA表达模式 在人类组织样本和动物模型中，PRC2是这一过程的主要调节者。 在这项提案中，我们的目标是通过探索MB的神经发育过程来治疗MB 自发成熟的机制，以确定PRC2通过以下途径调节的途径 具体目标：1)整合表观遗传机制和转录组的分子解剖 人髓母细胞瘤的原始成分，2)阐明EZH2在表观遗传调控中的作用 肿瘤细胞在SHH MB中的成熟，以及3)评估肿瘤血管靶向治疗的疗效和毒性 EZH2和Sonic Hedgehog(SHH)通路在SHH驱动的髓母细胞瘤中的抑制作用。我们将利用高- 分辨基因组学和表观遗传学技术，一种遗传相关的小鼠髓母细胞瘤模型 概述人类疾病，以及一种新的肿瘤血管特异性纳米粒给药平台 这使得它可以穿透血脑屏障。 我们的长期目标是确定诱导自然成熟的肿瘤选择性表观遗传策略。 这与目前髓母细胞瘤的护理治疗标准具有协同作用。如果我们的结果证明 有利的是，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.