Modeling pediatric glioma in human ES cells:mechanistic and therapeutic insights

在人类 ES 细胞中模拟儿科神经胶质瘤：机制和治疗见解

基本信息

批准号：
9317449
负责人：
VIVIANE TABAR
金额：
$ 39.24万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-18 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317449
关键词：
ACVR1 gene Age Age of Onset Amino Acid Substitution Binding Biological Models Biology Brain Stem Brain Stem Glioma Brain Stem Neoplasms Brain region Cancer Model Cell Death Cells Child Childhood Brain Neoplasm Childhood Glioma Chromatin Collaborations Complex Data Development Diagnosis Diffuse intrinsic pontine glioma Disease Disease model Drug Targeting Endocrine Epigenetic Process Event FGFR1 gene Gene Mutation Genetic Genetic Engineering Genetic Variation Glioma Goals Growth Histologic Histone H3 Histones Human In Vitro Libraries Location Lysine MEN1 gene Maintenance Malignant Neoplasms Menin Methionine Modeling Molecular Multiple Partners Mutation Neoplasms Oncogenic Pathway interactions Patients Pattern Phenotype Polycomb Preclinical Drug Evaluation Process Proteins Receptor Protein-Tyrosine Kinases Reporting Role Scientist Signal Pathway Somatic Mutation Stem cells Syndrome Tail Therapeutic Therapeutic Studies Tissues Tumor Biology Tumor Suppressor Proteins Tumor Tissue Variant Work base brain cell design effective therapy experience gain of function genome-wide analysis glioma cell line human embryonic stem cell in vivo inhibitor/antagonist insight kinase inhibitor leukemia novel protein protein interaction stem cell differentiation tool treatment strategy tumor tumor growth tumor progression

项目摘要

Abstract / Project Summary DIPGs are rapidly lethal brain tumors of childhood. The majority of patients die within a year or two of diagnosis, as there is no effective treatment for this devastating disease. Their critical location in the brainstem has long prohibited access to tumor tissue. Recently, sequencing studies revealed novel histone mutations consisting of single amino acid substitutions in the tail of the histone H3 variants. A pattern of exclusive co-occurrence of histone mutations with specific signaling pathway alterations as well as age of onset and brain region alterations emerged. Taking advantage of these data and of the strict developmental window of the tumors, our team has built what is effectively the first genetically-engineered human ES cell-based model of a tumor. The model yielded tumors that recapitulated the genetic, transcriptomal, epigenetic and histological features of the disease, thus providing valuable tools for the study of the disease. Genome wide studies suggested that the histone mutation led to a resetting of the developmental status of the cells to an earlier more primitive stem cell state. Importantly, our modeling system served as an effective platform for drug screens, leading to the identification of a novel protein –protein interaction network as a key component of the proliferative and growth machinery of these tumors, centered on the protein menin. Menin is a unique protein with multiple partners; it is oncogenic in the context of the MLL rearranged leukemias. Our data show that silencing menin or inhibiting its MLL interaction with a menin inhibitor leads to a decrease in proliferation and increased cell death, a completely novel finding never reported in glioma, that raises the promise of a therapeutic strategy. The proposal aims to expand our hES modeling platform by building new models that are representative of the genetic diversity of the somatic mutations described in brainstem gliomas. We will also study the events downstream of the histone mutations, with emphasis on the molecular basis of the oncogenic role of menin. The ultimate goal is to develop a therapeutic strategy for DIPGs, taking advantage of newly synthesized menin inhibitors. Our studies should also contribute to developing hES cells into a more widely applicable platform for cancer modeling capitalizing on their many advantages, including access to an unlimited supply of stage appropriate human cells for mechanistic or therapeutic studies, the ability to study tumor biology from the step of initiation to tumor maintenance, and the ease of implementing sophisticated genetic tools.

摘要 /项目摘要 DIPG是儿童期致命的脑肿瘤。大多数患者死于诊断的年或两年，因为这种毁灭性疾病没有有效的治疗方法。他们的长期以来，脑干中的关键位置已禁止进入肿瘤组织。最近，测序研究揭示了由单个氨基酸组成的新型组蛋白突变组蛋白H3变体的尾部取代。独家共同出现的模式带有特定信号通路改变以及发作年龄和大脑的Hisstone突变出现了区域改变。利用这些数据和严格的发展肿瘤的窗户，我们的团队已经建立了有效的第一个遗传工程的东西肿瘤的基于人类ES细胞的模型。该模型产生了概括的肿瘤遗传，转录组，表观遗传和组织学特征，因此提供研究该疾病的有价值的工具。基因组广泛的研究表明组蛋白突变导致将细胞的发育状态重置为更早的原始状态干细胞状态。重要的是，我们的建模系统是药物筛查的有效平台，导致将新型蛋白质 - 蛋白质相互作用网络鉴定为关键成分这些肿瘤的增殖剂和生长机制，以蛋白质为中心。 Menin是一种独特的蛋白质，具有多个伴侣。它在MLL的背景下是致癌的重新排列的白血病。我们的数据表明，使Menin沉默或抑制其与A的MLL相互作用梅宁抑制剂导致增殖减少和细胞死亡增加，这是一种完全新颖的发现从未在神经胶质瘤中报道，这增加了治疗策略的希望。该建议旨在通过建立新模型来扩展我们的HES建模平台代表了脑干中描述的体细胞突变的遗传多样性神经胶质瘤。我们还将研究Hisstone突变下游的事件，重点是梅宁致癌作用的分子基础。最终目标是开发治疗性利用新合成的MENIN抑制剂的DIPG策略。我们的研究还应有助于将HES细胞开发成更广泛的适用癌症建模平台利用其许多优势，包括访问适当的人类细胞无限供应机械或治疗研究，从启动到肿瘤维持的步骤研究肿瘤生物学的能力，并易于实施复杂的遗传工具。