Abramson Cancer Center Support Grant

艾布拉姆森癌症中心支持补助金

• 批准号: 10469216
• 负责人: ROBERT H VONDERHEIDE
• 金额: $ 36.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/10469216
• 关键词: Address; Adolescent and Young Adult; Adult; Adult Glioma; Age; Automobile Driving; Cancer Center Support Grant; Caring; Cause of Death; Cell Nucleus; Cells; Childhood; Childhood Glioma; Clinical; Clinical Trials; Computer Analysis; Epigenetic Process; Evolution; Genetic; Glioblastoma; Glioma; Heterogeneity; Malignant Neoplasms; Malignant neoplasm of brain; Modality; Molecular; Patients; Phenotype; Population; Recurrence; Research; Residual Tumors; Resistance; Sampling; Specimen; Systems Biology; Testing; Therapeutic; cancer cell; cohort; multiple omics; novel therapeutics; programs; therapy resistant; tumor; tumor heterogeneity

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).

项目总结 儿童、青少年和青壮年(Aya)和成人的高级别胶质瘤(HGG/GBM) 群体代表一个共同的未得到满足的治疗需求，其基础是细胞的异质性 这些肿瘤及其对治疗的抗药性和残留病，是导致死亡的最终原因。 尽管这一年龄段进行了大量的分子研究，但高级别胶质瘤和胶质母细胞瘤 尽管复发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可获得性有限问题 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 儿童脑胶质瘤复发。这一努力是同类研究计划中的第一次。 在整个儿科、阿雅、成人HGG/GBM环境中实施希望工程(儿科和阿雅高级 神经胶质瘤OMICS项目)代表儿科/AYA努力，以及项目CARE(细胞分析 抵抗和进化)代表了成人的努力。我们的中心假设是 遗传、TME相互作用和表观遗传多样性驱动细胞可塑性并推动胶质瘤适应 治疗和肿瘤内表型的异质性。为了解决这个问题，我们将解决 HGG样本之间的遗传、表观遗传和表型异质性，有以下两个 独立但相互关联的目标：儿科和AYA中癌细胞的单细胞多组测序 高级别胶质瘤(目标1)；儿童非免疫微环境的单核测序 和Aya高级别胶质瘤(Aim 2)。