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: 10446714
• 负责人: Praveen B. Raju
• 金额: $ 74.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446714
• 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; 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; 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 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.

项目摘要/摘要 髓母细胞瘤是最常见的小儿脑肿瘤，约占所有大脑的20％ 儿童肿瘤。髓母细胞瘤高度恶性且难以治疗，近30％受影响 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育的儿童大脑的不利副作用。 幸存者患有记忆，注意力缺陷，智商和学习障碍，甲状腺和学习障碍，甲状腺和 性腺功能障碍（不育）和生长延迟。据估计，髓母细胞瘤不到20％ 到达成年的幸存者可以过独立的生活。因此，更有效且毒性更少 对于髓母细胞瘤的患者来说，非常需要。 髓母细胞瘤由原始的未分化神经细胞组成，但一些肿瘤显示 自发成熟成类似于神经元分化过程的非增殖性脑样组织 在正常的大脑发育期间。我们假设自发成熟是表观遗传驱动的。经过 阐明自发成熟的驱动因素，可以确定新的治疗途径 我们诱导诊所的成熟，并将恶性肿瘤迫使良性脑样组织。我们表明 髓母细胞瘤的成熟和原始区域具有明显不同的RNA表达模式，并且 PRC2是人类组织样品和动物模型中此过程的主要调节剂。 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）评估肿瘤血管靶向的疗效和毒性 EZH2和Sonic刺猬（SHH）途径在SHH驱动的髓母细胞瘤中抑制。我们将利用高 分辨率基因组学和表观遗传学技术，这是一种与遗传相关的小鼠髓母细胞瘤模型 概括了人类疾病，以及一种新型的肿瘤脉管系统特异性纳米粒子药物输送平台 这可以穿透血脑屏障。 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 这与当前髓母细胞瘤的护理疗法协同作用。我们的结果应该证明 有利，我们设想适用于髓母细胞瘤和其他脑肿瘤的患者。