CCSG supplement: HOPE/CARE

CCSG 补充：希望/关怀

• 批准号: 10467882
• 负责人: PETER W PISTERS
• 金额: $ 10万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467882
• 关键词: Aberrant DNA Methylation; Address; Adolescent and Young Adult; Adult; Adult Glioma; Age; Automobile Driving; Binding Sites; Cancer Center Support Grant; Caring; Cause of Death; Cell Differentiation process; Cell Nucleus; Cells; Childhood; Childhood Glioma; Clinical; Clinical Trials; Computer Analysis; DNA; Data; Disease; Enhancers; Epigenetic Process; Event; Evolution; Flow Cytometry; Freezing; Gene Activation; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Glioblastoma; Glioma; Heterogeneity; Hypermethylation; Induced Mutation; Link; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of brain; Medical Genetics; Methods; Methylation; Modality; Molecular; Multiomic Data; Mutation; NF1 gene; NOTCH1 gene; Oncogene Activation; Output; PIK3CA gene; Patients; Pattern; Phenotype; Population; Recurrence; Research; Residual Tumors; Resistance; Resolution; Role; Sampling; Site; Somatic Mutation; Specimen; Systems Biology; Technology; Testing; Therapeutic; Time; Variant; base; cell type; cohort; exome; genetic selection; genome sequencing; methylome; multimodality; multiple omics; mutant; novel therapeutics; programs; promoter; stem; stem cells; therapy resistant; transcriptome; transcriptomics; tumor; tumor heterogeneity

Project Glioblastoma CARE: “Cellular Analysis of Resistance and Evolution”. Proposal for Year 3 extension. High grade gliomas (HGG/GBM) across the pediatric, adolescent and young adult (AYA), and adult populations represent a common unmet therapeutic need underpinned by the cellular heterogeneity of these tumors and its contribution to treatment resistance and residual disease, the ultimate cause of death. Despite numerous molecular studies across this age spectrum, high grade glioma and glioblastoma at recurrence remain poorly characterized, despite being the context for most clinical trials. This project leverages multi-institutional specimen cohorts that addresses the limited availability of paired longitudinal patient specimens and combines such cohorts with state-of-the-art single-cell platforms to profile adult and pediatric gliomas through recurrence. This effort represents a first in kind continuum of research initiative across the pediatric, AYA, adult HGG/GBM landscape with Project HOPE (Pediatric and AYA High-Grade Glioma Omics Project) representing the pediatric/AYA effort, and Project CARE (cellular analysis of resistance and evolution) representing the adult effort. Our central hypothesis is that the interplay between genetic, TME interactions and epigenetic diversity drive cellular plasticity and fuels gliomas adaptation to therapy and intra-tumoral phenotypic heterogeneity. To address this, we will tackle the integration of genetic, epigenetic, and phenotypic heterogeneity across IDH-wildtype GBM and IDH-mutant gliomas clinical samples, with the following three independent yet interrelated aims: examine the role of epigenetic alterations, such as aberrant DNA methylation, in cellular programs driving GBM resistance to therapy (Aim 1); define the impact of somatic mutations as a function of GBM cellular states and their role in driving resistance (Aim 2); expand our cohort to additional classes of disease, namely interrogate primary and recurrent IDH-mutant gliomas (Aim 3).

Project Glioblastoma CARE：“Cellular Analysis of Resistance and Evolution”.第三年提案 扩展名. 儿童、青少年和年轻成人（AYA）以及成人的高级别胶质瘤（HGG/GBM） 人群代表了一种常见的未满足的治疗需求，其基础是细胞异质性， 这些肿瘤及其对治疗抵抗和残留疾病的贡献，最终导致死亡。 尽管在这个年龄范围内进行了大量的分子研究，高级别胶质瘤和胶质母细胞瘤在 尽管是大多数临床试验的背景，但复发的特征仍然很差。这个项目 利用多机构样本队列，解决配对纵向样本的有限可用性 患者样本，并将这些队列与最先进的单细胞平台相结合，以分析成人和 小儿胶质瘤复发。这一努力代表了第一次在实物连续研究倡议 在儿科、AYA、成人HGG/GBM领域，通过Project HOPE（儿科和AYA高级 神经胶质瘤组学项目）代表儿科/AYA的努力，和CARE项目（神经胶质瘤细胞分析）， 抵抗和进化）代表成人的努力。我们的核心假设是 遗传、TME相互作用和表观遗传多样性之间的相互作用驱动细胞可塑性和燃料 胶质瘤对治疗的适应性和肿瘤内表型异质性。为了解决这个问题，我们将 解决IDH-野生型GBM中遗传、表观遗传和表型异质性的整合， IDH突变型神经胶质瘤临床样本，具有以下三个独立但相互关联的目的： 表观遗传学改变的作用，如异常DNA甲基化，在细胞程序驱动GBM 对治疗的抗性（目标1）;将体细胞突变的影响定义为GBM细胞状态的函数 以及它们在驱动耐药性中的作用（目标2）;将我们的队列扩展到其他疾病类别，即 询问原发性和复发性IDH突变型神经胶质瘤（目标3）。