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

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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.