Stanford Cancer Institute Project HOPE: The Pediatric/AYA Omics Project

摘要/摘要 儿童、青少年和青壮年(Aya)和成人人群中的高级别胶质瘤(HGG/GBM) 代表了由这些肿瘤的细胞异质性支撑的共同的未得到满足的治疗需求 其对治疗耐药和残留病的贡献是最终的死亡原因。尽管有许多 在这一年龄段的分子研究中，复发的高级别胶质瘤和胶质母细胞瘤仍然很差。 尽管是大多数临床试验的背景，但仍具有特征性。该项目利用多个机构 样本队列，解决配对的纵向患者样本和联合样本的有限可用性 这样的队列使用最先进的单细胞平台来描述成人和儿童胶质瘤的复发情况。 这项工作代表了儿科、AYA、成人HGG/GBM的第一个同类连续研究计划 景观与希望工程(儿科和阿亚高级胶质瘤OMICS项目)代表 代表成人的儿科/Aya努力和Project Care(抵抗和进化的细胞分析) 努力。在资助的前两年，我们进行了恶性肿瘤的单核rna测序。 儿童和青年纵向标本中的细胞、免疫细胞和非免疫微环境细胞 成人和青少年(Aya)高级别胶质瘤和成人IDH-野生型胶质母细胞瘤标准前和标准后 关爱疗法。我们优先考虑来自儿童和Aya年龄组(0-39岁)的临床注释样本 成人胶质母细胞瘤，IDH野生型(47-67岁)。我们对患者匹配的肿瘤进行了分析 来自初诊和复发的样本。我们的总体假设是，专注于解剖所有癌症 通过单细胞RNA测序了解肿瘤内的细胞及其微环境将导致更好的 了解这些疾病并开发更有效的治疗方法以改善治疗结果 病人。 为了继续我们对这一假设的追求，我们提出了以下目标： (1)对儿童和青壮年的癌细胞进行单细胞多组学测序 青少年(Aya)高级别胶质瘤 (2)对儿科和阿亚的非免疫微环境进行单细胞测序 高级别胶质瘤 (3)打造独特的数据共享和数据共享平台，整合希望工程成果 利用蛋白质组学数据集和在成人样本上进行的类似研究。

Summary/Abstract 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. In the first 2 years of funding, we performed single-nucleus RNA sequencing (snRNA-seq) of malignant cells, immune cells and non-immune microenvironmental cells in longitudinal samples of pediatric and young adult and adolescent (AYA) high-grade gliomas and in adult IDH-wildtype glioblastoma, pre- and post-standard of care therapy. We prioritized clinically annotated samples from children and AYA age groups (0 - 39 years of age) and adult glioblastoma, IDH wildtype (47-67 years of age). We profiled patient-matched tumor specimens from initial diagnosis and relapse. Our overall hypothesis is that a focus on dissecting all cancer cells within a tumor as well as its microenvironment by single-cell RNA sequencing will lead to a better understanding of these diseases and the development of more effective therapeutics to improve outcomes for patients. To continue our pursuit of this hypothesis, we propose the following aims: (1) Perform single cell multi-omics sequencing of cancer cells in pediatric and young adult and adolescent (AYA) high-grade gliomas (2) Perform single cell sequencing of the non-immune microenvironment of pediatric and AYA high-grade gliomas (3) Create unique Data Commons and Data Sharing platform to integrate Project Hope results with proteomics dataset and similar research done on adult samples.