Inducing neural maturation in medulloblastoma by targeting EZH2

通过靶向 EZH2 诱导髓母细胞瘤神经成熟

• 批准号: 10416148
• 负责人: Praveen B. Raju
• 金额: $ 46.09万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416148
• 关键词: Adult; Affect; Animal Model; Area; Attentional deficit; Benign; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Maturation; Child; Childhood Brain Neoplasm; Classification; Clinic; Clinical; Complex; DNA Sequence Alteration; Deposition; Development; Diagnosis; Dissection; Drug Delivery Systems; EZH2 gene; Endocrine; Epigenetic Process; Functional disorder; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Histology; Histone H3; Human; Infertility; International; Learning Disabilities; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Memory impairment; Meta-Analysis; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neuraxis; Neuronal Differentiation; Neuropil; Pathologist; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pediatric Neoplasm; Pediatric Oncology Group; Penetration; Phenotype; Polycomb; Process; Prognosis; Proteins; Radiation therapy; Recurrence; Regimen; Reporting; Resolution; Role; SHH gene; Second Primary Cancers; Signal Pathway; Sonic Hedgehog Pathway; Subgroup; Survival Rate; Survivors; Techniques; Testing; Therapeutic; Thyroid Gland; Time; Tissue Sample; Tissues; Toxic effect; Tumor Biology; Undifferentiated; brain tissue; chemotherapy; cognitive disability; differential expression; epigenetic regulation; epigenomics; exome sequencing; gain of function; gene repression; genome-wide analysis; human disease; human tissue; improved; inhibitor/antagonist; loss of function; medulloblastoma; mouse model; nanoparticle drug; neoplastic cell; neuroblast; novel; novel therapeutics; preclinical study; primary endpoint; prospective; relating to nervous system; side effect; standard of care; targeted treatment; therapy outcome; therapy resistant; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy; tumor; tumor heterogeneity

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.

项目摘要/摘要 髓母细胞瘤是最常见的小儿脑肿瘤，约占20％ 儿童的所有脑肿瘤。髓母细胞瘤高度恶性，难以治疗，导致近30％ 受影响的患者无法治愈。此外，即使是治愈的儿童也患有严重的长期 缺陷主要是由于放射治疗对生长和发展的负面影响 孩子的大脑。幸存者患有记忆和注意力缺陷，智商减少，认知和学习 残疾，甲状腺和性腺功能障碍（不育）和生长延迟。据估计，不到20％ 到达成年的髓母细胞瘤幸存者能够过独立的生活。因此，更多 对于髓母细胞瘤患者而言，非常需要有效且毒性较小的疗法。 髓母细胞瘤由原始的未分化神经细胞组成，而某些肿瘤显示焦点 自发成熟到类似于神经元分化的非增殖性脑样组织 正常大脑发育过程中发生的过程。我们假设自发成熟是 表观遗传驱动并通过阐明自发成熟的驱动因素，新型治疗途径 可以确定，这将使我们能够在诊所诱导成熟并将恶性肿瘤施加到 良性脑状组织。我们表明，髓母细胞瘤的成熟和原始区域明显 不同的RNA表达模式，PRC2是人类组织中此过程的主要调节剂 样品和动物模型。 在此提案中，我们旨在通过探索劫持MB治疗的神经发育过程 自发成熟的机制，以识别PRC2通过以下方式调节的途径 具体目的：1）整合成熟和成熟和转录组学的分子解剖 人类髓母细胞瘤的原始成分，2）阐明EZH2在表观遗传调节中的作用 小鼠SHH MB中的肿瘤细胞成熟，3）评估肿瘤脉管系统的功效和毒性 SHH驱动的髓母细胞瘤中有针对性的EZH2和Sonic刺猬（SHH）途径抑制。我们将 利用高分辨率基因组学和表观遗传学技术，这是一种遗传相关的小鼠髓母细胞瘤 概括人类疾病的模型和一种新型的肿瘤脉管系统特异性纳米粒子药物 传递平台，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 与当前髓母细胞瘤的护理标准疗法协同成熟。应该结果 证明是有利的，我们设想适用于髓母细胞瘤和其他脑肿瘤的患者。