PROJECT SUMMARY High grade gliomas (HGG/GBM) across 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. Project HOPE team consists of: (1) Dana Farber Cancer Institute: single cell genomics and analyses (Mariella Filbin); (2) UCSF: single cell genomics and analyses (Aaron Diaz); (3) Stanford: tissue procurement (Michelle Monje); (4) CHOP: tissue procurement (Adam Resnick); (5) Data Commons and NCI CDRC and CCDI interoperability and integration (CHOP: Adam Resnick); (6) Project Coordinator: W. K. Alfred Yung, MD, MD Anderson Cancer Center. We propose the following aims: Aim 1 - Single cell multi-omic sequencing of cancer cells in pediatric and AYA high-grade gliomas. Aim 2 - Single nucleus sequencing of the non-immune microenvironment of pediatric and AYA high-grade gliomas. Aim 3 - Data Commons and Data Sharing. Overall, by leveraging this unique single-cell multi-omics toolkit for Year 3 of HOPE, and integrating our findings with project CARE, we will provide novel insights into developmental, genetic, TME, and epigenetic drivers of cellular states that underlie HGG evolution and resistance to existing therapies across all age groups.

Knowledge of high-grade pediatric glioma at recurrence is limited. We address this gap in knowledge by profiling longitudinal human pediatric high-grade glioma specimens using single-cell genomics.