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: 10700897
• 负责人: Praveen B. Raju
• 金额: $ 69.97万
• 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/10700897
• 关键词: Adult; Affect; Animal Model; Area; Attentional deficit; Benign; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Maturation; Central Nervous System; 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; Leptomeninges; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Memory; Meta-Analysis; Methylation; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neuronal Differentiation; Neuropil; Pathologist; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pediatric Neoplasm; Pediatric Oncology Group; Penetration; Phenotype; Polycomb; Process; Prognosis; Proliferating; 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; efficacy evaluation; 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; neural; neuroblast; novel; novel therapeutics; preclinical study; primary endpoint; prospective; side effect; standard of care; synergism; 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.

项目概要/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高且难以治疗，导致近30%的患者罹患髓母细胞瘤。 患者无法治愈。此外，即使是被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儿童生长发育中的大脑产生不良副作用。 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（不孕）和生长延迟。据估计，少于 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、毒性更小的治疗方法 髓母细胞瘤患者非常需要。 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 在正常的大脑发育过程中。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，从而允许 我们在临床上诱导成熟，迫使恶性肿瘤转化为良性脑样组织。我们表明 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， PRC2 是人体组织样本和动物模型中这一过程的主要调节者。 在本提案中，我们的目标是通过探索 MB 治疗的神经发育过程 自发成熟机制，通过以下方式确定 PRC2 调节的途径 具体目标：1）将表观遗传机制和转录组学的分子解剖整合到成熟和 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 小鼠 SHH MB 中肿瘤细胞的成熟，以及 3) 评估肿瘤血管靶向药物的功效和毒性 SHH 驱动的髓母细胞瘤中的 EZH2 和 Sonic Hedgehog (SHH) 通路抑制。我们将利用高 分辨率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 概括了人类疾病，以及一种新型肿瘤血管特异性纳米颗粒药物输送平台 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 与当前髓母细胞瘤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，我们预计它适用于髓母细胞瘤和其他脑肿瘤患者。