A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

Cell Rep. 2020 Jul 14;32(2):107897. doi: 10.1016/j.celrep.2020.107897.

Abstract

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.

Keywords: biobank; combination therapy; data integration; glioblastoma; multi-omics; p53 reactivators; patient-derived cells; primary cells; proteasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Bortezomib / pharmacology
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Gene Regulatory Networks / drug effects
  • Genetic Heterogeneity
  • Genome, Human
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Mice, Inbred BALB C
  • Molecular Targeted Therapy*
  • Mutation / genetics
  • Precision Medicine*
  • Proteasome Inhibitors / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proteasome Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Bortezomib