Abramson Cancer Center Support Grant

项目摘要 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驱动细胞可塑性，并促进胶质瘤适应 治疗和肿瘤内表型异质性。为解决这一问题，我们将解决以下问题： HGG样本的遗传、表观遗传和表型异质性， 独立但相互关联的目标：儿科和AYA中癌细胞的单细胞多组学测序 高级别胶质瘤（Aim 1）;儿童非免疫微环境的单核测序 和AYA高级别胶质瘤（Aim 2）。

PROJECT SUMMARY 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 HGG samples, with the following two independent yet interrelated aims: Single cell multi-omic sequencing of cancer cells in pediatric and AYA high-grade gliomas (Aim 1); Single nucleus sequencing of the non-immune microenvironment of pediatric and AYA high-grade gliomas (Aim 2).