Abstract 6346: Optimizing precision combination therapies based on single-cell profiling of brain tumor biopsies

Abstract

Abstract Glioblastomas (GBM) display dramatic levels of intra-tumoral heterogeneity. This heterogeneity contributes significantly to resistance to standard and emerging treatments. As a result, GBM remains the deadliest primary tumor of the adult brain. Moreover, most preclinical studies of GBM use models of primary GBM, most studies of clinical specimens use tissue derived from primary GBMs, despite the fact that most clinical trials enroll patients at recurrence. There is a paucity of information about recurrent GBM. To address these critical barriers, we devised a strategy to optimize precision drug combinations based on an understanding of a patient's intratumor heterogeneity, ascertained via single-cell profiling. We conducted single-nucleus RNA sequencing (snRNA-seq) and/or single-nucleus assay for transposon-accessible chromatin (snATAC-seq) sequencing for 16 recurrent GBMs. For 6 of these cases we also derived cell lines from patient biopsies. We identified lineage hierarchies of proliferating cells and their more differentiated progeny. Based on this, we performed an in vitro drug-combination screen using FDA-approved chemotherapies, targeting pathways learned from these single-cell signatures. We found that targeting distinct cellular states in the inferred lineage hierarchy of a patient's tumor provides a more complete treatment than targeting one state alone. Additionally, we will present the results of our ongoing in vivo validation activities and profiling efforts. This work presents a novel paradigm for identifying precision combinations of chemotherapies targeted to phenotypes learned from single-cell profiling of a patient's tumor biopsy. Citation Format: Husam Babikir, Lin Wang, Karin Shamardani, Francisca Catalan, Gary Kohanbash, Manish K. Aghi, Joanna J. Phillips, Aaron A. Diaz. Optimizing precision combination therapies based on single-cell profiling of brain tumor biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6346.