CCSG supplement: HOPE/CARE

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Project Glioblastoma CARE: “Cellular Analysis of Resistance and Evolution”. Proposal for Year 3 extension. 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 IDH-wildtype GBM and IDH-mutant gliomas clinical samples, with the following three independent yet interrelated aims: examine the role of epigenetic alterations, such as aberrant DNA methylation, in cellular programs driving GBM resistance to therapy (Aim 1); define the impact of somatic mutations as a function of GBM cellular states and their role in driving resistance (Aim 2); expand our cohort to additional classes of disease, namely interrogate primary and recurrent IDH-mutant gliomas (Aim 3).