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20% 所有儿童脑瘤。髓母细胞瘤恶性程度高，治疗难度大，导致近30% 受影响的病人是无法治愈的。此外，即使被治愈的儿童也会遭受严重的长期 不足主要是由于放射治疗对生长发育的负面副作用 孩子的大脑。幸存者患有记忆力和注意力缺陷，智商下降，认知和学习 残疾、甲状腺和性腺功能障碍(不孕症)和生长迟缓。据估计，不到20% 成年期的髓母细胞瘤幸存者能够独立生活。因此，更多 髓母细胞瘤患者非常需要有效且毒性小的治疗方法。 虽然髓母细胞瘤由原始的未分化神经母细胞组成，但一些肿瘤显示病灶 自发成熟成类似神经元分化的非增殖性脑样组织 在正常大脑发育过程中发生的过程。我们假设自然成熟是 表观遗传驱动并通过阐明自发成熟的驱动因素，新的治疗途径 将允许我们在临床上诱导成熟，并迫使恶性肿瘤进入 良性的类脑组织。我们发现髓母细胞瘤的成熟区和原始区域有明显的 不同的RNA表达模式，并且在人类组织中，PRC2是这一过程的主要调节者 样本和动物模型。 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)评估肿瘤血管系统的疗效和毒性。 定向抑制EZH2和Sonic Hedgehog(SHH)途径抑制SHH驱动的髓母细胞瘤。我们会 利用高分辨率基因组学和表观遗传学技术，发现一种与基因相关的小鼠髓母细胞瘤 重述人类疾病的模型和一种新的肿瘤血管特异性纳米药物 允许穿透血脑屏障的输送平台。 我们的长期目标是识别肿瘤选择性表观遗传策略，以诱导自发 与当前髓母细胞瘤护理治疗标准协同的成熟度。我们的结果应该是 事实证明是有利的，我们预计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.